Rare Disease Discussions

Shunji Tomatsu, MD, PhD, Professor and Head, Nemours Children’s Health, Delaware, USA; Alessandra d’Azzo, PhD, Emerita Faculty, Genetics, St. Jude Children’s Research Hospital, Tennessee, USA; Merve Emecen Sanli, MD, Associate Professor, Department of Pediatrics, University of Texas Southwestern Medical Center, Texas, USA; and Ryan Colburn, patient with Pompe disease and president of Odimm Inc, discuss new and emerging gene therapies for lysosomal disorders.This continuing education activity is provided through collaboration between the Lysosomal and Rare Disorders Research and Treatment Center (LDRTC), CheckRare CE, and AffinityCE. This activity provides continuing education credit for physicians, physician assistants, nurses, nurse practitioners, and genetic counselors. A statement of participation is available to other attendees.To obtain CME/CE credit, please visit https://checkrare.com/learning/p-grids2025-session6-current-issues-in-gene-therapies-for-lysosomal-disorders/  Learning ObjectivesDescribe current and emerging gene therapy data in lysosomal disorders and its clinical relevanceDescribe role of patients in gene therapy developmentFacultyShunji Tomatsu, MD, PhD, Professor and Head, Nemours Children’s HealthAlessandra d’Azzo, PhD, Emerita Faculty, Genetics, St. Jude Children’s Research HospitalMerve Emecen Sanli, MD, Associate Professor, Department of Pediatrics, University of Texas Southwestern Medical CenterRyan Colburn. Odimm, Inc.DisclosuresAffinityCE staff, LDRTC staff, planners, and reviewers, have no relevant financial relationships with ineligible companies to disclose. Faculty disclosures, listed below, will also be disclosed at the beginning of the Program.Shunji Tomatsu, MD, PhD Dr. Tomatsu has received the following grants: Morquio Foundations and families: Scarlett Grifith, Bennett, A Cure for Roberts, and Morquio Conference; MPS Societies: Japanese, National, and Austrian; NIH grants: 1-R01-HD102545, NIH, NICHD, Tomatsu (PI), 1R01HD104814-01A1, NIH, NICHD, Langan, T.J. (PI), Role: Site-PI, R43HD114328-01, NIH, ACOSTA, WALTER (PI), Role: site PI, 1R43AR084638-01, NIH, MOUNZIH, KHALID (PI); Foundation of NIH: FNIH RFP NUMBER: 2022-BGTC-005 Tomatsu (PI). Alessandra d’Azzo, PhDDr. D’Azzo has no relevant financial relationships to disclose.Merve Emecen Sanli, MDDr. Sanli has no relevant financial relationships to disclose.Ryan ColburnMr. Colburn has an advisory, consulting and/or project based relationship or stock holding with: Abeona Therapeutics, Amicus Therapeutics, Astellas Gene Therapies, Avidity Biosciences, Bayer, Catalyst Pharmaceuticals, Denali Therapeutics, M6P Therapeutics, Sangamo Therapeutics, Sanofi, Solid Biosciences.Mitigation of Relevant Financial RelationshipsAffinityCE adheres to the ACCME’s Standards for Integrity and Independence in Accredited Continuing Education. Any individuals in a position to control the content of a CME activity, including faculty, planners, reviewers, or others, are required to disclose all relevant financial relationships with ineligible entities (commercial interests). All relevant conflicts of interest have been mitigated prior to the commencement of the activity. Conflicts of interest for presenting faculty with relevant financial interests were resolved through peer review of content by a non-conflicted reviewer.Accreditation and Credit DesignationPhysiciansThis activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of AffinityCE and the LDRTC. AffinityCE is accredited by the ACCME to provide continuing medical education for physicians.AffinityCE designates this enduring activity for a maximum of 1 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.Physician AssistantsAffinityCE designates this enduring activity for a maximum of 1 AMA PRA Category 1 Credits™. Physician Assistants should claim only the credit commensurate with the extent of their participation in the activity.NursesAffinityCE is accredited as a provider of nursing continuing professional development by the American Nurses Credentialing Center’s Commission on Accreditation (ANCC). This activity provides a maximum of 1 hours of continuing nursing education credit.Nurse PractitionersAffinityCE designates this enduring activity for a maximum of 1 AMA PRA Category 1 Credits™. Nurse practitioners should claim only the credit commensurate with the extent of their participation in the activity.Genetic CounselorsAffinityCE designates this enduring activity for a maximum of 1 AMA PRA Category 1 Credits™. Genetic Counselors should claim only the credit commensurate with the extent of their participation in the activity.Other ProfessionalsAll other health care professionals completing this continuing education activity will be issued a statement of participation indicating the number of hours of continuing education credit. This may be used for professional education CE credit. Please consult your accrediting organization or licensing board for their acceptance of this CE activity. Participation CostsThere is no cost to participate in this activity.CME InquiriesFor all CME policy-related inquiries, please contact us at ce@affinityced.comSend customer support requests to cds_support+ldrtc@affinityced.com

Duarte C. Barral, PhD, Associate Professor, NOVA Medical School, NOVA University of Lisbon, Portugal; Nuno Raimundo, PhD, Associate Professor, Department of Cellular and Molecular Physiology; Penn State College of Medicine, Pennsylvania, USA; Betul Celik, PhD, Postdoctoral Fellow, Nemours Children’s Health, Delaware, USA; and Gregory Newby, PhD, Assistant Professor, Department of Genetic Medicine, Johns Hopkins School of Medicine, Maryland, USA,discuss the principles of theranostics and its application in lysosomal disorders.This continuing education activity is provided through collaboration between the Lysosomal and Rare Disorders Research and Treatment Center (LDRTC), CheckRare CE, and AffinityCE. This activity provides continuing education credit for physicians, physician assistants, nurses, nurse practitioners, and genetic counselors. A statement of participation is available to other attendees.To obtain CME/CE credit, please visit https://checkrare.com/learning/p-grids2025-session5-theranostics-and-lysosomal-disorders/ Learning ObjectivesDescribe lysosomal and inter-organelle mechanisms that contribute to pathology in lysosomal disorders, and how these pathways are being leveraged for diagnostic and therapeutic applications.Describe current and emerging theranostic strategies for lysosomal disorders.FacultyDuarte C. Barral, PhD, Associate Professor, NOVA Medical School, NOVA University of Lisbon, Nuno Raimundo, PhD, Associate Professor, Department of Cellular and Molecular Physiology; Penn State College of MedicineBetul Celik, PhD, Postdoctoral Fellow, Nemours Children’s HealthGregory Newby, PhD, Assistant Professor, Department of Genetic Medicine, Johns Hopkins School of MedicineDisclosuresAffinityCE staff, LDRTC staff, planners, and reviewers, have no relevant financial relationships with ineligible companies to disclose. Faculty disclosures, listed below, will also be disclosed at the beginning of the Program.Duarte C. Barral, PhD Dr. Barral’s group receives grant support from Sea4Us.Nuno Raimundo, PhDDr. Raimundo has no relevant financial relationships to disclose.Betul Celik, PhDDr. Celik has no relevant financial relationships to disclose.Gregory Newby, PhDDr. Newby has no relevant financial relationships to disclose.Mitigation of Relevant Financial RelationshipsAffinityCE adheres to the ACCME’s Standards for Integrity and Independence in Accredited Continuing Education. Any individuals in a position to control the content of a CME activity, including faculty, planners, reviewers, or others, are required to disclose all relevant financial relationships with ineligible entities (commercial interests). All relevant conflicts of interest have been mitigated prior to the commencement of the activity. Conflicts of interest for presenting faculty with relevant financial interests were resolved through peer review of content by a non-conflicted reviewer.Accreditation and Credit DesignationPhysiciansThis activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of AffinityCE and the LDRTC. AffinityCE is accredited by the ACCME to provide continuing medical education for physicians.AffinityCE designates this enduring activity for a maximum of 1 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.Physician AssistantsAffinityCE designates this enduring activity for a maximum of 1 AMA PRA Category 1 Credits™. Physician Assistants should claim only the credit commensurate with the extent of their participation in the activity.NursesAffinityCE is accredited as a provider of nursing continuing professional development by the American Nurses Credentialing Center’s Commission on Accreditation (ANCC). This activity provides a maximum of 1 hours of continuing nursing education credit.Nurse PractitionersAffinityCE designates this enduring activity for a maximum of 1 AMA PRA Category 1 Credits™. Nurse practitioners should claim only the credit commensurate with the extent of their participation in the activity.Genetic CounselorsAffinityCE designates this enduring activity for a maximum of 1 AMA PRA Category 1 Credits™. Genetic Counselors should claim only the credit commensurate with the extent of their participation in the activity.Other ProfessionalsAll other health care professionals completing this continuing education activity will be issued a statement of participation indicating the number of hours of continuing education credit. This may be used for professional education CE credit. Please consult your accrediting organization or licensing board for their acceptance of this CE activity. Participation CostsThere is no cost to participate in this activity.CME InquiriesFor all CME policy-related inquiries, please contact us at ce@affinityced.comSend customer support requests to cds_support+ldrtc@affinityced.com

Oral Alpan, MD, Immunologist, Amerimmune, Virginia, USA; Svenja Keller, PhD student, University of Zurich, Switzerland; Shoshana Revel-Vilk, MD, PhD, Director, Gaucher Unit & Pediatric Hematology/Oncology Unit, Shaare Zedek Medical Center, Jerusalem, Israel; Patrick Deegan, MD, Consultant Metabolic Physician, University of Cambridge, UK; and Ravi Kamath, MD, PhD, Head of Musculoskeletal Radiology, Inova Health System, Virginia, USA, discuss the applications of AI in the diagnosis and treatment of lysosomal disorders.This continuing education activity is provided through collaboration between the Lysosomal and Rare Disorders Research and Treatment Center (LDRTC), CheckRare CE, and AffinityCE. This activity provides continuing education credit for physicians, physician assistants, nurses, nurse practitioners, and genetic counselors. A statement of participation is available to other attendees.To obtain CME/CE credit, visit https://checkrare.com/learning/p-grids2025-session4-expanded-applications-of-ai-in-lysosomal-disorders/Learning ObjectivesDescribe how emerging AI and machine learning technologies are advancing disease modeling and biomarker development.Describe how emerging AI and machine learning technologies are advancing therapeutic target identification across lysosomal disorders.FacultyOral Alpan, MD, Immunologist, AmerimmuneSvenja Keller, PhD student, University of ZurichShoshana Revel-Vilk, MD, PhD, Director, Gaucher Unit & Pediatric Hematology/Oncology Unit, Shaare Zedek Medical CenterPatrick Deegan, MD, Consultant Metabolic Physician, University of CambridgeRavi Kamath, MD, PhD, Head of Musculoskeletal Radiology, Inova Health SystemDisclosuresAffinityCE staff, LDRTC staff, planners, and reviewers, have no relevant financial relationships with ineligible companies to disclose. Faculty disclosures, listed below, will also be disclosed at the beginning of the Program.Oral Alpan, MD Dr. Alpan has no relevant financial relationships to disclose.Svenja KellerMs. Keller has no relevant financial relationships to disclose.Shoshana Revel-Vilk, MD, PhDDr. Revel-Vilk receives grant/research support from Sanofi and Takeda. She is a member of the Speakers Bureau for Sanofi and Takeda, and a member of the Advisory Board for Takeda.Patrick Deegan, MDDr. Deegan is a consultant and advisory board member with Sanofi, Takeda, and Amicus.He also receives research support from Sanofi and Amicus.Ravi Kamath, MD, PhDDr. Kamath is on an advisory board for Intrinsic Therapeutics. He is also a consultant forSanofi, Takeda, and Spur Therapeutics.Mitigation of Relevant Financial RelationshipsAffinityCE adheres to the ACCME’s Standards for Integrity and Independence in Accredited Continuing Education. Any individuals in a position to control the content of a CME activity, including faculty, planners, reviewers, or others, are required to disclose all relevant financial relationships with ineligible entities (commercial interests). All relevant conflicts of interest have been mitigated prior to the commencement of the activity. Conflicts of interest for presenting faculty with relevant financial interests were resolved through peer review of content by a non-conflicted reviewer.Accreditation and Credit DesignationPhysiciansThis activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of AffinityCE and the LDRTC. AffinityCE is accredited by the ACCME to provide continuing medical education for physicians.AffinityCE designates this enduring activity for a maximum of 1 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.Physician AssistantsAffinityCE designates this enduring activity for a maximum of 1 AMA PRA Category 1 Credits™. Physician Assistants should claim only the credit commensurate with the extent of their participation in the activity.NursesAffinityCE is accredited as a provider of nursing continuing professional development by the American Nurses Credentialing Center’s Commission on Accreditation (ANCC). This activity provides a maximum of 1 hours of continuing nursing education credit.Nurse PractitionersAffinityCE designates this enduring activity for a maximum of 1 AMA PRA Category 1 Credits™. Nurse practitioners should claim only the credit commensurate with the extent of their participation in the activity.Genetic CounselorsAffinityCE designates this enduring activity for a maximum of 1 AMA PRA Category 1 Credits™. Genetic Counselors should claim only the credit commensurate with the extent of their participation in the activity.Other ProfessionalsAll other health care professionals completing this continuing education activity will be issued a statement of participation indicating the number of hours of continuing education credit. This may be used for professional education CE credit. Please consult your accrediting organization or licensing board for their acceptance of this CE activity. Participation CostsThere is no cost to participate in this activity.CME InquiriesFor all CME policy-related inquiries, please contact us at ce@affinityced.comSend customer support requests to cds_support+ldrtc@affinityced.com

Mia Horowitz, PhD, Tel Aviv University; Aitor Aguirre, PhD, Michigan State University, Michigan, USA; and Ying Sun, PhD, University of Cincinnati, discuss the use of organoid models in lysosomal disorder research and drug development.This continuing education activity is provided through collaboration between the Lysosomal and Rare Disorders Research and Treatment Center (LDRTC), CheckRare CE, and AffinityCE. This activity provides continuing education credit for physicians, physician assistants, nurses, nurse practitioners, and genetic counselors. A statement of participation is available to other attendees.To obtain CME/CE credit, visit https://checkrare.com/learning/p-grids2025-session3-organoids-and-lab-grown-models-in-lysosomal-disorders/Learning ObjectivesDescribe the use of heart organoid models to better understand the pathophysiology of lysosomal disorders and its clinical relevanceDescribe the use and application of brain organoid models in neuropathic Gaucher disease research and treatmentFacultyMia Horowitz, PhD, Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University.Aitor Aguirre, PhD, Associate Professor of Biomedical Engineering, Institute for Quantitative Health Science and Engineering, Chief, Division of Developmental and Stem Cell Biology (IQ), Director, MSU Stem Cell Core, Michigan State University.Ying Sun, PhD, Professor, Cincinnati Children’s Hospital Medical Center, University of Cincinnati.DisclosuresAffinityCE staff, LDRTC staff, planners, and reviewers, have no relevant financial relationships with ineligible companies to disclose. Faculty disclosures, listed below, will also be disclosed at the beginning of the Program.Mia Horowitz, PhDDr. Horowitz has no relevant financial relationships to disclose.Aitor Aguirre, PhDDr. Aguirre has no relevant financial relationships to disclose.Ying Sun, PhDDr. Sun receives research support from Enkefalos Biosciences and Yuhan Corporation.Mitigation of Relevant Financial RelationshipsAffinityCE adheres to the ACCME’s Standards for Integrity and Independence in Accredited Continuing Education. Any individuals in a position to control the content of a CME activity, including faculty, planners, reviewers, or others, are required to disclose all relevant financial relationships with ineligible entities (commercial interests). All relevant conflicts of interest have been mitigated prior to the commencement of the activity. Conflicts of interest for presenting faculty with relevant financial interests were resolved through peer review of content by a non-conflicted reviewer.Accreditation and Credit DesignationPhysiciansThis activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of AffinityCE and the LDRTC. AffinityCE is accredited by the ACCME to provide continuing medical education for physicians.AffinityCE designates this enduring activity for a maximum of 1 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.Physician AssistantsAffinityCE designates this enduring activity for a maximum of 1 AMA PRA Category 1 Credits™. Physician Assistants should claim only the credit commensurate with the extent of their participation in the activity.NursesAffinityCE is accredited as a provider of nursing continuing professional development by the American Nurses Credentialing Center’s Commission on Accreditation (ANCC). This activity provides a maximum of 1 hours of continuing nursing education credit.Nurse PractitionersAffinityCE designates this enduring activity for a maximum of 1 AMA PRA Category 1 Credits™. Nurse practitioners should claim only the credit commensurate with the extent of their participation in the activity.Genetic CounselorsAffinityCE designates this enduring activity for a maximum of 1 AMA PRA Category 1 Credits™. Genetic Counselors should claim only the credit commensurate with the extent of their participation in the activity.Other ProfessionalsAll other health care professionals completing this continuing education activity will be issued a statement of participation indicating the number of hours of continuing education credit. This may be used for professional education CE credit. Please consult your accrediting organization or licensing board for their acceptance of this CE activity. Participation CostsThere is no cost to participate in this activity.CME InquiriesFor all CME policy-related inquiries, please contact us at ce@affinityced.comSend customer support requests to cds_support+ldrtc@affinityced.com

Stephan Stern, PhD, DABT, Director of Research and Development, Nanotechnology Characterization Lab (NCL), Frederick National Laboratory for Cancer Research, Maryland, USA; and Ruben Boado, PhD, Professor of Medicine, University of California at Los Angeles, California, USA, discuss the use of nanotechnology in the treatment of lysosomal disorders.This continuing education activity is provided through collaboration between the Lysosomal and Rare Disorders Research and Treatment Center (LDRTC), CheckRare CE, and AffinityCE. This activity provides continuing education credit for physicians, physician assistants, nurses, nurse practitioners, and genetic counselors. A statement of participation is available to other attendees.To obtain CME/CE credit, visit https://checkrare.com/learning/p-grids2025-session2-nanotechnology-and-lysosomal-disorders/Learning ObjectivesDescribe recent advances in the use of nanotechnology to treat lysosomal disordersDescribe the role of nanotechnology in addressing unmet needs in lysosomal disordersFacultyStephan Stern, PhD, DABTDirector of Research and Development, Nanotechnology Characterization Lab (NCL), Frederick National Laboratory for Cancer ResearchRuben Boado, PhDProfessor of Medicine, University of California at Los AngelesDisclosuresAffinityCE staff, LDRTC staff, planners, and reviewers, have no relevant financial relationships with ineligible companies to disclose. Faculty disclosures, listed below, will also be disclosed at the beginning of the Program.Stephan Stern, PhD, DABTDr. Stern has no relevant financial relationships to disclose. Ruben Boado, PhDDr. Boado has no relevant financial relationships to disclose.Mitigation of Relevant Financial RelationshipsAffinityCE adheres to the ACCME’s Standards for Integrity and Independence in Accredited Continuing Education. Any individuals in a position to control the content of a CME activity, including faculty, planners, reviewers, or others, are required to disclose all relevant financial relationships with ineligible entities (commercial interests). All relevant conflicts of interest have been mitigated prior to the commencement of the activity. Conflicts of interest for presenting faculty with relevant financial interests were resolved through peer review of content by a non-conflicted reviewer.Accreditation and Credit DesignationPhysiciansThis activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of AffinityCE and the LDRTC. AffinityCE is accredited by the ACCME to provide continuing medical education for physicians.AffinityCE designates this enduring activity for a maximum of 1 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.Physician AssistantsAffinityCE designates this enduring activity for a maximum of 1 AMA PRA Category 1 Credits™. Physician Assistants should claim only the credit commensurate with the extent of their participation in the activity.NursesAffinityCE is accredited as a provider of nursing continuing professional development by the American Nurses Credentialing Center’s Commission on Accreditation (ANCC). This activity provides a maximum of 1 hours of continuing nursing education credit.Nurse PractitionersAffinityCE designates this enduring activity for a maximum of 1 AMA PRA Category 1 Credits™. Nurse practitioners should claim only the credit commensurate with the extent of their participation in the activity.Genetic CounselorsAffinityCE designates this enduring activity for a maximum of 1 AMA PRA Category 1 Credits™. Genetic Counselors should claim only the credit commensurate with the extent of their participation in the activity.Other ProfessionalsAll other health care professionals completing this continuing education activity will be issued a statement of participation indicating the number of hours of continuing education credit. This may be used for professional education CE credit. Please consult your accrediting organization or licensing board for their acceptance of this CE activity. Participation CostsThere is no cost to participate in this activity.CME InquiriesFor all CME policy-related inquiries, please contact us at ce@affinityced.comSend customer support requests to cds_support+ldrtc@affinityced.com

Behzad Najafian, MD, Professor, Department of Laboratory Medicine & Pathology, Department of Medicine at the University of Washington, Washington, USA discusses the use of artificial intelligence in identifying and managing lysosomal disorders.This continuing education activity is provided through collaboration between the Lysosomal and Rare Disorders Research and Treatment Center (LDRTC), CheckRare CE, and AffinityCE. This activity provides continuing education credit for physicians, physician assistants, nurses, nurse practitioners, and genetic counselors. A statement of participation is available to other attendees.To obtain CME/CE credit, visit https://checkrare.com/learning/p-grids2025-session1-ai-in-medicine-transforming-the-landscape-of-tissue-based-diagnostics/Learning ObjectivesDescribe recent advances in the applications of AI in lysosomal disorder diagnosis and its clinical relevanceFacultyBehzad Najafian, MD Professor, Department of Laboratory Medicine & Pathology, Department of Medicine, University of WashingtonDisclosuresAffinityCE staff, LDRTC staff, planners, and reviewers, have no relevant financial relationships with ineligible companies to disclose. Faculty disclosures, listed below, will also be disclosed at the beginning of the Program.Behzad Najafian, MDDr. Najafian is on the Advisory Board/Consultant for Sanofi, Amicus, Avrobio, 4DMT,Sangamo, Freeline, AceLink, Relay, CRISPR, ELOXX, SPARK, UNIQURE. He receives grants/research support from Amicus. Mitigation of Relevant Financial RelationshipsAffinityCE adheres to the ACCME’s Standards for Integrity and Independence in Accredited Continuing Education. Any individuals in a position to control the content of a CME activity, including faculty, planners, reviewers, or others, are required to disclose all relevant financial relationships with ineligible entities (commercial interests). All relevant conflicts of interest have been mitigated prior to the commencement of the activity. Conflicts of interest for presenting faculty with relevant financial interests were resolved through peer review of content by a non-conflicted reviewer.Accreditation and Credit DesignationPhysiciansThis activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of AffinityCE and the LDRTC. AffinityCE is accredited by the ACCME to provide continuing medical education for physicians.AffinityCE designates this enduring activity for a maximum of 1 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.Physician AssistantsAffinityCE designates this enduring activity for a maximum of 1 AMA PRA Category 1 Credits™. Physician Assistants should claim only the credit commensurate with the extent of their participation in the activity.NursesAffinityCE is accredited as a provider of nursing continuing professional development by the American Nurses Credentialing Center’s Commission on Accreditation (ANCC). This activity provides a maximum of 1 hours of continuing nursing education credit.Nurse PractitionersAffinityCE designates this enduring activity for a maximum of 1 AMA PRA Category 1 Credits™. Nurse practitioners should claim only the credit commensurate with the extent of their participation in the activity.Genetic CounselorsAffinityCE designates this enduring activity for a maximum of 1 AMA PRA Category 1 Credits™. Genetic Counselors should claim only the credit commensurate with the extent of their participation in the activity.Other ProfessionalsAll other health care professionals completing this continuing education activity will be issued a statement of participation indicating the number of hours of continuing education credit. This may be used for professional education CE credit. Please consult your accrediting organization or licensing board for their acceptance of this CE activity. Participation CostsThere is no cost to participate in this activity.CME InquiriesFor all CME policy-related inquiries, please contact us at ce@affinityced.comSend customer support requests to cds_support+ldrtc@affinityced.com

Alan Beggs, PhDDirector of the Manton Center for Orphan Disease ResearchSir Edwin and Lady Manton Professor of Pediatrics, Boston Children's HospitalHarvard Medical School, Boston, MA, USA Julie A. Parsons, MDHaberfield Endowed Chair in Pediatric Neuromuscular DisordersProfessor of Clinical Pediatrics and NeurologyUniversity of Colorado School of Medicine, Children's Hospital ColoradoAurora, CO, USAThe ASPIRO Clinical Trial is on clinical hold since September 2021. In this part, Doctors Beggs and Parsons will discuss key issues on gene therapy development.Question: Is there a standardized immunomodulation regimen being considered for gene therapy?Julie A. Parsons, MDAs I mentioned, right now, I think there are a number of different concepts that are being utilized. We don't really have a recommended standard regimen at this point. There are a number of different trials that are ongoing looking at trying to answer this question. In some of the clinical trials, there is an immune modulating regimen that is being put in place but being looked at. There isn't anything that we have as a standard at this moment for all gene transfer therapies, but I'm hopeful that we will come up with something that really makes sense in each patient population as we go forward with specific gene transfer therapies.Question: What are the long-term implications, safety and efficacy of a one-time gene therapy in pediatric patients with neuromuscular diseases?Alan Beggs, PhDOne question is the efficacy. For example, Donovan Decker's story, he had an experimental treatment of one muscle. It was a phase one safety trial, and he knew that nothing was going to come of it in terms of direct benefit to him. As a result, though, 25, 30 years later, he still has a tighter against AAV vectors. He's not a candidate for gene therapy under current protocols, although there's a lot of work going on to redosing. But for now, it's a one-time treatment. What you get is what you get, and there's not a chance to go back and do it again.The other question is durability. We really don't know about the long-term durability for these treatments. I should say that, for example, in the studies that we did, David Mack, who's here in the audience, managed a dog colony for a dog model of excellent tubular myopathy. Those animals lived 10 years in a... We never used the C-word, but they were cured. They were healthy, happy, normal dogs who would have had to be put down at 6 months of age otherwise. And then, as we heard, I'll let you talk about the concern for unanticipated SAEs as time goes on, but I think there's other aspects we need to think about.Julie A. Parsons, MDYeah. I think that this is really the key question that all of us are going to need to help answer over the next several years. Efficacy, we're looking at outcomes, and outcomes come in a variety of flavors. I think we do a decent job with motor outcomes. We don't do a decent job with some other outcomes. I think we need to look more broadly in terms of what we mean in terms of beneficial outcomes and really take some of those cues from the patients themselves about if these are efficacious treatments, because, again, the risk is high as we deliver these agents, and we need to know that it's worth it to the patients and families.In terms of safety, we're working on it. There are all sorts of things that are coming forward as issues with these patients. I think that collectively as a community, that our responsibility is to follow patients for the long term. There are lots of registries and outcome studies. We're not very good as a community about reporting adverse events to central groups. We're not great about broadcasting that to each other in real-time. I think those are things that we really need to work on as a community in terms of helping with the safety issues so that we all have a communal better understanding of what some of those issues are.

Julie A. Parsons, MD Haberfield Endowed Chair in Pediatric Neuromuscular DisordersProfessor of Clinical Pediatrics and NeurologyUniversity of Colorado School of Medicine, Children's Hospital ColoradoAurora, CO, USAHow have programs adapted to the experiences from clinical trials? I'm just looking at SMA because we've had SMA. We've had onasemnogene around for the longest period of time. We want to always confirm a diagnosis and know that the patient is right. We do antibody testing for these disorders prior to delivering the AAV therapies. We have to know that the product that is incredibly expensive is handled appropriately by the institution. Dealing with the pharmacy, making certain that you handle the agent properly, patients need to be pretreated at this point with prednisone, and that really has to happen so that you know that they're ready for treatment, that they don't have any infections prior to treatment.Then we need to monitor and provide medication and follow-up afterwards. As I said, I think this is really, really important to make sure that you're connected well with the patient. If you live in an area as we do, that has a huge catchment area with patients that come from hundreds of miles away, sometimes they need to stay with us for a period of time, so that we can ensure the safety and follow-up of these patients after we deliver gene therapies.Again, a recurring theme is the patients that you're treating who are not in a clinical trial are not the homogeneous, well-selected patients. It's really all actors. The population that you're treating commercially is very different. We're now moving into treating patients with larger body masses and older ages. We don't always know, because those patients haven't really been included in the clinical trials. We don't really know what some of the effects are going to be with that group of patients as well.I am a neurologist. I am not an immunologist. I have had to learn a lot of immunology at this point, but it's still not sufficient. I think that we also need to reach out to our subspecialist colleagues who really do have more experience than we do to try to help us with some of these issues, because as we look at these viral vector capsids and the transgenes, we have to say, is there something that we can do to mitigate the immune response that we're seeing when we're giving massive doses of these agents and really taxing the immune system in our patients?Looking at possibilities, we give steroids, and that's really what we've done. That was what was done in the early clinical trials with MENDEL. It's like, okay, prednisone, that's all we have to do is we give steroids and everybody will be fine. That really isn't maybe the answer. As we have more information, we know that we're going to start with steroids, but we're really going to look at, is there a way to block both the B-cell response, the T-cell response? Is there something that we can do so that we don't have to sit on the edge of our seats and not sleep for months after we treat these patients?At least in a trial, was done looking at patients who were treated just with corticosteroids. Those patients had rapid increases in IgM and IgG. There's complement activation. Both the adaptive and the acute immune responses are triggered. That's really what we're doing as standard practice right now, but in the trial looking at treating patients and pretreating patients with rituximab blocking B cells and sirolimus and corticosteroids, then no significant change in IgM, IgG.Is that something that we should be doing? I think that some of the clinical trials that are being set up are looking at instituting some of these immune-modulating features to see whether or not their outcomes are improved. Can we do anything proactively to prevent our patients from having some of these very severe events or fatalities? I think that's really what we need to be looking at now. I think we are looking at that as a community, and to me, is a story that is still unfolding in terms of how we keep our patients safe.In the next part, Doctors Beggs and Parsons will discuss key issues on gene therapy development.

Julie A. Parsons, MDHaberfield Endowed Chair in Pediatric Neuromuscular DisordersProfessor of Clinical Pediatrics and NeurologyUniversity of Colorado School of Medicine, Children's Hospital ColoradoAurora, CO, USANow, with our collective experience, we can at least put together the information that we have in terms of what can we expect and what's the timeline that we expect in terms of our patients having reactions. I will tell you, and I've said this multiple times, when I deliver a gene transfer therapy, I hold my breath for 2 months. Now, maybe it's going to have to be extended to a year, but it's typically at least for 2-3 months. It's like, okay, what's going to happen? You sit on the edge of your seat on pins and needles, going, "Is this kid going to be okay or not?" I think that's the appropriate response to have in terms of the light of things that have happened over time. We have to be really careful.We have a little bit of a framework now to say, when do we need to be really excited? We know that our patients, most all of them, are going to develop a transaminitis, and that ends up happening early on, but we get a couple of peaks. We get really excited that the 4-8 week time point with transaminitis looking for liver failure.The cholestatic liver disease that happened in the patients with X-linked MTM happened a little bit later, so Week 2, all the way out to six months afterwards. The acute cardiomyopathy a little bit earlier, so we're looking a little bit earlier for that effect. TMA, usually the end of the first week to about 2 weeks is when we would expect that to come in. Then the transgene-related myositis and immune-mediated myocarditis, weeks, maybe 2 to a couple of months.How do we adapt our gene transfer programs to the clinical trial experience? I think that there are a couple of points that are important. One is that the outline that I showed you, there are some disease-agnostic issues that come up with transaminitis, with TMA. I think there are some final common pathways related to the immune responses that we see with these patients. Then there are going to be some disease-specific disorders that are going to come up with each of these therapies and agents.We need to have good communication, honestly, in real-time. I still don't know that we have a good mechanism for that as a community, but to share these adverse events that come up so that we can all learn as a collective about what to expect, what to anticipate, and how to best take care of our patients. We know now how we need to monitor patients closely from a laboratory standpoint, from a clinical exam standpoint, and we really need to work on how are we going to mitigate some of these risk issues that we have with these patients.I think the collaborative aspect, particularly at meetings like this, is important. Last year, for the people that were at MDA, you remember that we really spent a lot of time looking at gene transfer delivery. Many of us got together as providers and actually met together to say, "Is there something that we can think about in terms of best practice or consensus in terms of how we would want to manage patients or how we'd want to share information?"Now, actually, on the MDA website, we really do have some guidelines, and there will be a publication coming out shortly that we'll have this available to everybody again. It's not necessarily the right answer, but it's at least from a collective experience, what's the best way that we can go forward? Some of the suggestions were that the adverse events right now, we can put them into some a predictable timeline, but we don't really know all the risks at the time of dosing.We know that gene transfer therapy can be safe for the right patient at the right time for the right disorder. That's really what we want to do. There's a Neurotherapeutic window between efficacy and toxicity. How are we adjusting that? What are we working on to make sure that we're getting that right? The preclinical data is helpful, but it's never the full story. Any time we go from a homogeneous population that we see in a clinical trial to a heterogeneous population, as we throw this out to the world, we're going to have new issues that arise, and we need to be aware and ready for those.We want to be able to predict what happens, but we can't always do that. Then follow-up is so important. The post-marketing study, sharing adverse events, sharing experiences, I think, is really important as well. Clinicians really should be familiar with this entire field before ever delivering gene transfer therapy. I don't think that every site should be delivering gene transfer. I think that from an institutional standpoint, you need to be ready. You need to have a team who knows what they're doing and knows how to handle the issues and the problems, or you need to have lifelines set up in advance if you're going to deliver these treatments.

Julie A. Parsons, MDHaberfield Endowed Chair in Pediatric Neuromuscular DisordersProfessor of Clinical Pediatrics and NeurologyUniversity of Colorado School of Medicine, Children's Hospital ColoradoAurora, CO, USAThe gene transfer trials for musculoskeletal disorders, if we look at musculoskeletal and neurologic disorders, we really do have the highest success rate in terms of treatment, but we also carry the highest incidence of treatment-emergent severe adverse events. And why is that true? Yesterday, when we were hearing about Donovan as well, we looked and said, When the first gene transfer therapies were started, he had a single muscle that was injected.When we look at Luxturna, we injected the retina. Now, what is happening with these disorders is that we're giving these huge, massive doses of viral vector to patients. There haven't been a lot of gene transfer therapies that have reached the market. But you saw yesterday, so many gene transfer therapies being worked on, but there are very few that have actually come to market. There are a couple of reasons for that.One is with the indications that we have, we know that the musculoskeletal disorders are most likely to achieve benefit, but there are the high risk of severe adverse events. Route of Administration, IV, for most of our disorders is the way we're going. We may end up having some Intrathecal therapies as well that are coming on board, but right now it's IV, and that means, a huge dose of this viral vector and antigenic risk that is being administered.In the vector design now, we actually have more specific vectors as well as promoters that are being utilized to really target specific tissues, so that we're able to focus in a little bit more on the tissues that we want to have affected. And then the dose has gone from these little tiny local injections to really systemic, much broader. And now our patients, are larger. So we're giving a viral genome per kilo dose that is just massive as we look at that.Then there really are challenges in terms of the translation of clinical trials to commercial treatment with these agents. And we don't always know, we're not always great when we do tests in clinical trials in small populations, about when that's broadened to the commercial availability and we hit larger heterogeneous populations.There are safety issues arising from these therapies, and I think that we have some experience now, certainly with the three diseases that I mentioned at the beginning, in terms of collecting some data and information to have a little bit more of an idea what to expect. Although to me, the recurring esteem is always, expect the unexpected. Because we still are learning about this. Hepatotoxicity. We know that transaminitis is something that we see in almost every gene transfer therapy that has been delivered, and we have to watch really, really closely and follow our patients closely for this. We also have to select patients that we don't think have risk for additional liver injury or underlying liver pathology, because as we found out in the XLMTM boys, we missed that. Thrombotic Microangiopathy. We look at this disorder. We've had deaths in SMA from TMA. We have Duchenne patients that have had TMA.This is scary because as many of us as clinicians who have treated patients, you know that we end up getting thrombocytopenia. So is that it this time, or are they going to be fine, or the platelet is going to go back to normal? This is another one that we have to watch really, really closely for. Cardiac Toxicity. We have had cardio myositis. We've had deaths from cardiac toxicity.Something really, really important for us to think about. In little kids, vomiting could be a sign of cardiac myositis. And for most of us who've treated patients with gene transfer therapy, what's one of the first issues that you get?You get nausea of vomiting, they don't feel good. So is that myocarditis or is it just a standard side effect that we're seeing with treatment? Importantly, as we discovered, there actually can be an immune response to the transgene. It's not just the viral vector capsid, it's actually the transgene as well. That was discovered in patients who were treated for Duchenne. So that's a really important thing in terms of looking now at what's our patient's selection and how do we pick the right patients.Next part, Dr. Parsons will discuss understanding and preparing risk factors associated with AAV gene therapies.

Julie A. Parsons, MD Haberfield Endowed Chair in Pediatric Neuromuscular DisordersProfessor of Clinical Pediatrics and NeurologyUniversity of Colorado School of Medicine, Children's Hospital ColoradoAurora, CO, USAAs we talk about the gene transfer therapies and the modalities that we have to use, it's really interesting. Yesterday, with our keynote speaker, you could see this logarithmic growth of the use of gene transfer therapies for these disorders. If you look at the Venn diagram, you can see that really 27% almost of gene transfer therapies that are used are in musculoskeletal and neurology. For many of us as neurologists, we also take care of metabolic disorders.We really own right now this landscape, and of course, our two approved modalities are Onasemnogene and Delandistrogene. We're going to look at three different disorders, monogenic disorders, monogenic diseases, to typify what we look at in terms of some of the risks and benefits of these treatments. SMA, Duchenne, and X-linked myotubular myopathy are all rare disorders. They're all diseases that have a high unmet medical need and a significant disease burden.I think they're all good in terms of typifying where we are clinically with these disorders. The first question is, is it worth it? Are these effective treatments? We know from looking at the information about SMA that just looking early on, we know that if we treat kids early, that we do see a marked improvement in motor scores for kids that are treated early with Onasemnogene.In Duchenne, we have information that there is at least some improvement in the 4-5-year-olds in terms of motor skills treated with Delandistrogene. In terms of X-linked MTM, which was a very dramatic improvement, you could see that for boys who were basically traked, vented, and had no mobility, the bottom line, the blue line, is actually looking at ventilator dependence. Are they effective? Yeah, they're effective, but then we have to say, okay, what's the downside?The downside is that there's tremendous risk associated with treatment with these agents. If we really look at the sobering facts, we know that with SMA, there have been deaths, there have been fatalities related to thrombotic microangiopathy to patients who have liver failure, a couple of patients have died. With Onasemnogene, this is 4,000 plus doses that have so far been given. With Duchenne, unfortunately, many of us got the letter yesterday talking about an additional death in a patient treated with commercial Delandistrogene.We also know with some of the other agents, like fordadistrogene, patient died of heart failure, cardiac arrest, another patient who had acute respiratory syndrome with pulmonary edema. Again, we look at this and say this is significant. With X-linked MTM, as Alan said, there were some unanticipated deaths, four deaths from patients who ended up having cholestatic liver diseases that really wasn't anticipated prior to the patients being treated with the animal models and all that we had. Then many of you have heard about the patient with Rett syndrome who had a systemic hyperinflammatory syndrome. Again, these are rare disorders. They have a high disease burden, but the risk of treatment is significant.In the next part, Dr. Parsons discuss factors impacting safety and efficacy of AAV-mediated gene therapies.

Alan Beggs, PhDDirector of the Manton Center for Orphan Disease ResearchSir Edwin and Lady Manton Professor of Pediatrics, Boston Children's HospitalHarvard Medical School, Boston, MA, USAThe challenges that you've heard about are real. Some of them I think we could have foreseen others. There was no way to know until we actually started treating patients in clinic. But we now know that there are immune responses and also responses just to the viral load. As Julie mentioned, we're giving massive doses to these patients on the order of one times ten to the 14 viral genomes per kilogram.Think about the fact that when these capsids are manufactured, there's a certain percentage of empty capsid. The amount of protein that's being delivered to these patients can be massive. One of the approaches to mitigate some of the risk would be to lower the dose. While early studies demonstrated that in order to get adequate delivery to skeletal muscle, you need to give these very large doses. But what if we could engineer a viral capsid that would be potent at lower doses?There has been quite a bit of research in this area that's ongoing, and some new next generation vectors that are just starting to enter the clinic. In particular, there are a class of Myotropic viral vectors or capsids so-called RGD vectors. RGD refers to arginine, glycine, and aspartic acid, which are three residues which, when present at a particular point in the viral capsid proteins interact with integrin receptors that are specific for skeletal muscle. These viral capsids home to skeletal muscle and can deliver their genetic payload at much lower doses. There was one group of these developed in Germany by Theo Grimm's lab.These were the so-called AAV Myos, and simultaneously in Boston at the Broad Institute, a group of capsids was developed that were called Myo AAV. These were both based off of an AAV nine backbone. It's basically an AAV nine legacy vector with these three amino acids changed. Now Solid Biosciences also has their own independently derived vector that I believe is also an RGD vector. These vectors give us the potential then for more efficient and specific delivery to muscle cells.They may or may not target the liver depending on the particular virus. Some of them the risk to the liver is mitigated by delivering a lower dose. You can also develop these vectors in a way that will be liver targeted, that specifically less of it gets delivered to the vectors. These would be really, in my mind potentially third generation vectors.Strategies, there are a number of strategies. You heard about the immunomodulation regimens. I just talked about optimizing vector design. Also, Doctor Parsons mentioned earlier the fact that where you deliver so zolgensma is delivered Intrathecally. We get it to the place we need it, and we're less likely to have off target effects through other tissues.Then improved manufacturing is very important. I mentioned the fact that every viral preparation contains empty capsids. There are ways to minimize the production of empty capsids, and also effective ways to filter out and remove those empty capsids. This is actually a very important aspect that is being developed further by the CMO community. Then in summary, I think it's important to take a holistic approach when we're thinking about the development of AAV based gene therapies for neuromuscular disease.It starts from the fact that for any given disease we're interested in, we need to define the genetic etiology. Since these are gene directed therapies. We need to pay careful attention to the preclinical animal models. How accurately do they really reflect the human condition? Or are there potentially responses in our human patients that we haven't experienced in the animals? It's important to understand the natural history and the patient population.Recognize that there's extensive heterogeneity, not just in age and severity, but also potentially in underlying susceptibilities in our patients. We have a group of toxicities that we know about and can anticipate. But as Julie was saying, you need to be really careful and think about any potential unexpected SAEs. And then finally I mentioned the manufacturing aspect, the development of newer vectors and quality control aspects that go into making a safe and effective therapeutic.In the next part. Doctor Parsons will discuss clinical safety and efficacy observed in AAV mediated gene therapy programs in DMD, SMA, and XLMTM.

Alan Beggs, PhDDirector of the Manton Center for Orphan Disease ResearchSir Edwin and Lady Manton Professor of Pediatrics, Boston Children's HospitalHarvard Medical School, Boston, MA, USA Julie A. Parsons, MDHaberfield Endowed Chair in Pediatric Neuromuscular DisordersProfessor of Clinical Pediatrics and NeurologyUniversity of Colorado School of Medicine, Children's Hospital ColoradoAurora, CO, USADoctors Beggs and Parsons discuss the current status of gene therapies in rare neuromuscular disorders in this eight part podcast series. This is derived from the symposium that was presented at the MDA 2025 conference in Dallas, Texas, in March 2025 and is intended for healthcare professionals only. This podcast includes information about investigational compounds that do not yet have a regulatory approval or authorization for a specific indication. The safety and efficacy of the agents under investigation have not been established. In contents of this podcast, shall not be used in any manner to directly or indirectly promote or sell the product for unapproved uses. The ASPIRO clinical trial is on clinical hold since September 2021.In this part, Doctor Beggs will provide an explanation of AAV-mediated gene therapies.Alan Beggs, PhDAAV vectors, which I'm going to be talking about more today, or Adeno associated viral vectors are small viruses. Their DNA gets delivered into the cell and remains extrachromosomal. There are very rare occasional integrations, but the risk of oncogenesis as a result is significantly lower as a consequence of remaining extrachromosomal, though, we do have to think about what happens as the cells divide and potentially the durability of treatment is more limited.There have been a lot of movement and development over the years, starting back in the 1980s when the first AAV genomes were isolated and sequenced. This led to a development of methods to produce recombinant AAVs that would lack the genes necessary for viral replication, but contain a therapeutic gene you wish to deliver. Through this, the structure of AAVs have been developed. There have been isolation of a number of naturally occurring variants. You've heard of AAV8, AAV9, also RH 74, derived from a rhesus monkey for the RH. These have all been used in clinical trials. Then at the end I'll talk a little bit about directed evolution methods to actually engineer capsids with particular properties that are beneficial.Throughout this we've identified some of the issues that arise in this. It was initially thought that AAV vectors were non-immunogenic, but in fact there are immune responses not just to the viral payload to the therapeutic protein, but also to the viral vectors, and you're going to hear about that from Doctor Parsons. Over time, as we've come to understand these challenges, we've also been developing approaches to mitigate them. In terms of clinical trials and treatments, the very first studies were done back in the 1970s.By the early 2000, the very first clinical therapeutic was approved in China. It was actually an oncolytic virus carrying a p53 gene to treat head and neck cancers. By now there are over 40 approved treatments for various types of AAV delivered gene therapies. Of course, the ones we know a lot about are Zolgensma, which was approved in 2019, and Elevidys, which was approved last year. A number of challenges and then also a number of approaches to overcome those challenges. First of all, the preclinical data are not always sufficient to predict the response of a human patient.For example, in X-linked myotubular myopathy we had mouse and dog models that exhibited a myopathy but nothing else, and yet when we treated human patients, we discovered that patients with X-linked myotubular myopathy actually had a previously only poorly recognized hepatopathology that led to potential liver consequences following gene therapy. The animal models don't always predict the clinical outcome in humans.Also, we have small disease populations. These are rare diseases. It's important to understand the natural history of these diseases, understand the heterogeneity among the clinical population. It's very important to engage with families and with patients and communities, understand who might be at increased risk to treatment with one of these. This feeds into safety considerations. We need to think also about some of the immune responses. I think we're starting to learn, for example, with the gene therapies for Duchenne, and we know this from SMA that some patients get into trouble and others don't. We need to understand why that may be, and we don't know about the long term effects. This has been very recent.

Drs. Beggs and Parsons discuss the current status of gene therapies in rare neuromuscular disorders in this eight-part podcast series. This is derived from the symposium that was presented at the MDA 2025 conference in Dallas, Texas, in March 2025, and is intended for healthcare professionals only.This podcast includes information about investigational compounds that do not yet have a regulatory approval or authorization for a specific indication. The safety and efficacy of the agents under investigation have not been established in contents of this podcast shall not be used in any manner to directly or indirectly promote or sell the product for unapproved uses. The ASPIRO clinical trial is on clinical hold since September 2021. In this part, Dr. Beggs will provide an introduction to gene-directed therapies.Alan Beggs, PhDI'm going to talk now about challenges, a little bit of background in the history and the development of AAV-mediated gene therapies, in particular for neuromuscular disorders. There are a lot of aspects about neuromuscular disease that make it a good group of conditions to target by gene replacement therapies. These are traditionally single gene disorders with known identified oftentimes protein deficiencies, so null mutations leading to lack of a protein.The primary tissue, the therapeutic target is a skeletal muscle, and so we can target that with the appropriate viral vectors. There's a major unmet medical need and substantial clinical burden for these conditions. As rare diseases, they place a very substantial burden on both health systems and patients, both economically and in terms of personal difficulties.I like to think about gene therapy, which is generically used for one category of this, to really think about gene-directed therapy. So this would be any therapy directed at the nucleic acids that are either encoding our DNA or are encoding the messenger RNA transcripts. So one approach to a gene-directed therapy can be directed at the RNA level. I think you're all familiar with the Exon-skipping approaches that target mRNA splicing.There are other methods for either knocking down toxic gain of function messenger RNAs, and there are methods now being developed to edit messenger RNAs. So this represents one class of gene therapy. You can also approach gene therapy at level of DNA by editing or changing the DNA in situ. So various CRISPR-Cas9-based approaches. There's now prime editing and other approaches for genetic engineering that target specific locations, often using bacteria endonucleasis that target with oligenucleotides that target specific sites.And then finally, there's gene replacement therapy, which is what we're going to spend most of our time on today, which really aims to not take away what's there and replace it, but to replace the missing protein product by providing a copy of the healthy or the complete wild type gene. Often, it can either be integrated into the chromosomes or remain extrachromosomal.So whether or not that happens really depends on the type of vector or approach you use. You can see here a number of different approaches for transferring in a therapeutic gene. The two most commonly used in clinical trials are lentivirus and AAV, and they have different strengths and weaknesses. Lentiviruses are used frequently for hematologic diseases.Lentivirus is a member of the retrovirus family and has the characteristic that it actually integrates into the DNA. So lentiviral treatments tend to be long-acting. However, they also suffer from the risk that by integrating into the DNA, you might have site-directed mutagenesis. And there have been known instances of cancers that arose through integration at the wrong site.In the next part, Dr. Beggs will cover the history and challenges in the development of AAV-mediated gene therapies.

Nicola Longo MD, PhD, and Mark Roberts, MDDrs. Longo and Roberts discussed the current status of gene therapies in rare neuromuscular disorders in this eight-part podcast series. This is derived from the symposium that was presented at World Symposium 2025 in San Diego, California on February 4th through 7th, 2025, and is intended for healthcare professionals only.This podcast includes information about investigational compounds that do not yet have a regulatory approval or authorization for a specific indication. The safety and efficacy of the agents under investigation have not been established and contents of this podcast shall not be used in any manner to directly or indirectly promote or sell the product for unapproved uses. The views, thoughts, and opinions expressed in this presentation belong solely to the author and are subject to change without notice. The contents of this presentation do not constitute an endorsement of any product or indication by Astellas.In this part, Doctors Roberts and Longo will discuss treatment with gene therapies.Question: Can one administer AAV-mediated gene therapy repeatedly?Mark Roberts, MDI think the traditional view would have been no. One can think of gene therapy as a silver bullet. Hopefully, it will reach its target. But if it's not effective, that bullet has been shot, the immunological response has occurred, and it means redosing, at least with that particular vector, may become difficult. But this situation is changing and evolving as we have better understanding of immunological modulation for repeat testing. We were discussing this yesterday evening, weren't we, Professor Longo?Nicola Longo MD, PhDCorrect. Basically, the current AAV-based gene therapy cannot be readministered. It is either effective, or it doesn't work. The other thing is that even though in theory, one could utilize a different AAV vector with different immunogenicity, there is many times cross-reactivity among the different adenovirus, adeno-associated viruses. Now, there are approaches in animal models in which you give a strong immune suppression to prevent the creation of the immune response against the adeno-associated virus, and at least in the animal model, it has been possible to give some of the gene therapy repeatedly.The second approach that is being tested is with gene correction therapy, in which by using an RNA guide and the CRISPR/Cas9 system delivered by lipid nanoparticles, you basically correct some of the effective genetic information. Obviously, since this is done by lipid nanoparticles and not by an AAV, the immunity that you create is really not there. You can give this one repeatedly, and in theory, it can be given more than one time. But again, you are absolutely correct. The current gene therapy cannot be given twice, and either it works or it doesn't work.Question:vWill gene-therapy-treated patients be able to go back to the standard of care or enzyme replacement therapy?Mark Roberts, MDI think when we're talking to patients about the potential benefits of gene therapy and the amelioration of the requirement to have these infusions on a regular basis of ERT, the hope is that will work, but they need to be reassured that we can potentially go back to the ERT. Gene therapy is an important treatment, but we don't know the destination of the patient at the beginning, and we have to make it available to them to go back to ERT.One of the crucial questions, of course, though, is the basis of the immunological reaction that perhaps prevented the gene therapy being effective. If it's against the viral vector, well, okay. If it's against the transgene, not great. If it's against the functional protein, that becomes more difficult. It is somewhat, I think at this time, to be fair to say to patients, think of gene therapy as a trial treatment. It is somewhat a leap of faith and an important observation, of course, for the patient community, but just be aware there may be downsides.Nicola Longo MD, PhDThey totally agree with Dr. Roberts. In general, they should be able to go back to enzyme replacement therapy if the gene therapy is not effective. However, what we are starting to appreciate is that we need to understand the immune response, not just to the enzyme replacement therapy, but also to gene therapy. What this field is doing is forcing geneticists to deal with the immune response. I feel that historically has not been dealt together. The two things need to be integrated. The advantage of the gene therapy is that the protein is produced endogenously. There should be the development of some degree of tolerance with time in the body towards the endogenous continuous production of a protein.Now, will that happen all the time? I still do not know. Again, we need to understand much better what is the integration of the immune system with the response to gene therapy in the ongoing clinical trials.

Nicola Longo MD, PhDProfessor and Vice Chair of Human Genetics,Allen and Charlotte Ginsburg Chair in Precision Genomic Medicine,Division of Clinical Genetics, Department of Human Genetics,University of California at Los Angeles (UCLA), Los Angeles, CA, USAMark Roberts, MDProfessor and Consultant Neurologist,University of Manchester, Manchester, UKResearch Lead for Adult Metabolic Medicine at Salford Care Organisation, Manchester, UKDrs. Longo and Roberts discussed the current status of gene therapies in rare neuromuscular disorders in this eight-part podcast series. This is derived from the symposium that was presented at World Symposium 2025 in San Diego, California on February 4th through 7th, 2025, and is intended for healthcare professionals only. This podcast includes information about investigational compounds that do not yet have a regulatory approval or authorization for a specific indication. The safety and efficacy of the agents under investigation have not been established and contents of this podcast shall not be used in any manner to directly or indirectly promote or sell the product for unapproved uses. The views, thoughts, and opinions expressed in this presentation belong solely to the author and are subject to change without notice. The contents of this presentation do not constitute an endorsement of any product or indication by Astellas. In this part, Dr. Longo will discuss ongoing gene therapies in lysosomal disorders.Nicola Longo MD, PhDI'm going to present to discuss some example of ongoing gene therapy for lysosomal disorder. There are gene therapy in development for both Fabry disease and some of this involve ex vivo gene therapy, many others involve systemic administration with an AAV, Gaucher disease type 1 that affect the periphery, and Gaucher disease type 2, where the replacement should occur within the central nervous system because this condition affects the brain. There is already one approved gene therapy for lysosomal disorder, which is for the early onset metachromatic leukodystrophy. This has been approved both in Europe and now even in the United States, which consists of ex vivo gene therapy with the administration of an extra gene that restore the function of the defective enzyme. Now there are many others that are ongoing for the same indication. There are gene therapy programs for GM1 and GM2 gangliosidosis, and at least one for Krabbe disease. It is important to know that some of these condition are actually included in the recommended uniform screening panel. Basically, we would have access to patients in a timely manner for some of these conditions. Then there are several gene therapy under development for the mucopolysaccharidoses, including MPS-IH, MPS-II, MPS-IIIA and MPS-IV.There are different type of lysosomal disorders, the one caused by mutation, integral membrane protein, not enzyme within the lysosome, but protein that are present on the membrane of the lysosome. This gene therapy that have been tested, it is for cystinosis, that it is caused by a defective lysosomal and for Danon disease, which is caused by a deficiency of an integral membrane part. Finally, one lysosomal disorder, which obviously seems a metabolic condition, but it is really not, is glycogen storage disease type 2 or Pompe disease, in which there is the intralysosomal accumulation of glycogen. There are several ongoing clinical trials to try to correct the problem in this condition.Now, I'm going to discuss some of the most advanced program in the lysosomal storage disorder. This include one for Fabry, which is on an accelerated approval pathway with phase 1 and 2 data, one for Gaucher disease type 1. Obviously, I'm going to discuss the one that has been already approved for metachromatic leukodystrophy. There is one for Hunter syndrome, and the difference of the one for Hunter syndrome, it is an example of the direct administration of gene therapy within the central nervous system.Finally, there is one ongoing for glycogen storage disease type 2 or Pompe disease in adult patients. In gene therapy for metachromatic leukodystrophy, it was the first gene therapy approved for lysosomal disorder in human, and this requires harvesting the CD34 cell from affected patient and then introducing the [inaudible 00:04:32] gene back in this cell, and then placing them back inside the patient again. This has been very effective in patients who were treated early, and obviously, the treatment needs to occur before there is irreversible brain damage in this patient.In the next part, Dr. Roberts and Longo will discuss treatment with gene therapies.

Nicola Longo MD, PhDProfessor and Vice Chair of Human Genetics,Allen and Charlotte Ginsburg Chair in Precision Genomic Medicine,Division of Clinical Genetics, Department of Human Genetics,University of California at Los Angeles (UCLA), Los Angeles, CA, USAMark Roberts, MDProfessor and Consultant Neurologist,University of Manchester, Manchester, UKResearch Lead for Adult Metabolic Medicine at Salford Care Organisation, Manchester, UKDrs. Longo and Roberts discussed the current status of gene therapies in rare neuromuscular disorders in this eight part podcast series. This is derived from the symposium that was presented at World Symposium 2025, in San Diego, California, on February 4th through 7th, 2025, and is intended for healthcare professionals only. This podcast includes information about investigational compounds that do not yet have a regulatory approval or authorization for a specific indication. The safety and efficacy of the agents under investigation have not been established, and contents of this podcast shall not be used in any manner to directly or indirectly promote or sell the product for unapproved uses. The views, thoughts and opinions expressed in this presentation belong solely to the author and are subject to change without notice. The contents of this presentation do not constitute an endorsement of any product or indication by Astellas. In this part, Dr. Longo will discuss gene replacement therapy in lysosomal disorders.Nicola Longo MD, PhDLet's go back a second to gene therapy. Gene therapy obviously has the potential of answering many of the questions that we still have open in lysosomal disorder because they could restore the activity of the lysosome pretty much in the whole body, or at least in multiple tissues. As you have seen, gene therapy can be done ex vivo where we take cells from the affected patient, we correct the gene, or we put an extra gene that it is functional. Then we put them back by doing a bone marrow transplant, basically creating space for the cells that have been genetically modified to correct the lysosomal defect. The biggest approach this is done usually by lentiviruses that they integrate inside the genome.

Nicola Longo MD, PhD, and Mark Roberts, MDDrs. Longo and Roberts discuss the current status of gene therapies in rare neuromuscular disorders in this eight-part podcast series. This is derived from the symposium that was presented at WORLDSymposium 2025 in San Diego, California on February 4th-7th 2025 and is intended for healthcare professionals only.This podcast includes information about investigational compounds that do not yet have a regulatory approval or authorization for a specific indication. The safety and efficacy of the agents under investigation have not been established and contents of this podcast shall not be used in any manner to directly or indirectly promote or sell the product for unapproved uses.The views, thoughts, and opinions expressed in this presentation belong solely to the author and are subject to change without notice. The contents of this presentation do not constitute an endorsement of any product or indication by Astellas. In this part, Dr. Longo will discuss the current treatment landscape and limitations in lysosomal disorders.Nicola Longo MD, PhDWhat I want to do today, is just place gene replacement therapy within the current landscape of lysosomal storage disorder treatment therapy. Gene therapy obviously has the potential of treating lysosomal disorder to correct the root cause of lysosomal storage disorder. The gene is defective, and what happen is that you can potentially either fix the gene or bypass the lack of the genetic product. But there are already therapies that are existing and are functioning. Obviously, in many cases, the lysosomal disorder is caused by defective production of an enzyme, which is defective.We can either replace the enzyme with enzyme replacement therapy, or provide chaperone for specific mutations that retain the synthesis of the enzyme, that however is not very functional. Another avenue that it is being reported is the utilization of substrate reduction therapy. A substrate accumulates, you prevent the synthesis of the substrate to reduce the accumulation of toxic material. What we know now is that this is not enough to produce many lysosomal disorders. In many cases, the lysosomal disorder result sometime in impairment of intracellular trafficking, and sometime in the function of other organelles.At the end, it results in the activation of the macrophagic system and inflammation. Already we have some therapy acting at this level. The end result of lysosomal storage disorder, there will be cell suffering and cell death, leading to a progression of the disease, and morbidity and mortality. Now, what therapy do we have available already? Obviously, hematopoietic stem cell transplantation has been around for quite some time.It has been the same thing that we do with gene therapy, except that instead of reintroducing the gene of the subject, we place gene of a subject who is not affected of the disease. This therapy has been proven effective in cases of MPS-1 and alpha-mannosidosis. But in many cases this has to be given way before symptoms start to be affected.Enzyme replacement therapy has been around for quite some time, starting with Gaucher disease, and now that it is available for a list of diseases that are there, so it's like Fabry, Gaucher, Pompe, different types of mucopolysaccharidosis, alpha-mannosidosis, acid lipase deficiency, 1 neuronal ceroid lipofuscinosis, and Niemann-Pick type A and B.Obviously the advantage of this therapy, they give back the enzyme that it is defective. But the disadvantage that many time they cannot enter specialized areas such as the brain. There is already the second generation of enzyme replacement therapy that it is available. With this second generation, some of the newer drugs are more effective in terms of cellular uptake, or in terms of having a prolonged half-life and prolonged activity.Then there are pharmacological chaperone therapy, and the one which is FDA approved is migalastat for Fabry disease, under study is ambroxol for Gaucher disease. The disadvantage of this therapy that only a selected number of mutations respond to this therapy.Substrate reduction therapy has been introduced for Gaucher disease many years ago with miglustat, and it was followed by eliglustat. Both of them are effective, and some of them more effective than other, simply because of the fewer side effects of eliglustat as compared to miglustat. But at the same time, eliglustat does not pass the blood brain barrier.\Finally, the newer agents that are already administered, N-acetyl-L-leucine and arimoclomol, both approved for Niemann-Pick type C, they act more on the downstream effect of the lysosomal storage disorder, either by stabilizing neuronal cell activity or by reducing the inflammation that is present in the brain.In the next part, Dr. Longo will discuss gene replacement therapy in lysosomal disorders.

Nicola Longo MD, PhD, and Mark Roberts, MDNicola Longo MD, PhDProfessor and Vice Chair of Human Genetics,Allen and Charlotte Ginsburg Chair in Precision Genomic Medicine,Division of Clinical Genetics, Department of Human Genetics,University of California at Los Angeles (UCLA), Los Angeles, CA, USAMark Roberts, MDProfessor and Consultant Neurologist,University of Manchester, Manchester, UKResearch Lead for Adult Metabolic Medicine at Salford Care Organisation, Manchester, UKDrs.Longo and Roberts discussed the current status of gene therapies in rare neuromuscular disorders in this eight-part podcast series. This is derived from the symposium that was presented at World Symposium 2025 in San Diego, California on February 4th through 7th, 2025 and is intended for healthcare professionals only.This podcast includes information about investigational compounds that do not yet have a regulatory approval or authorization for a specific indication. The safety and efficacy of the agents under investigation have not been established and contents of this podcast shall not be used in any manner to directly or indirectly promote or sell the product for unapproved uses. The views, thoughts, and opinions expressed in this presentation belong solely to the author and are subject to change without notice. The contents of this presentation do not constitute an endorsement of any product or indication by Astellas.In this part, Dr. Roberts will discuss lessons learned from gene therapy trials.Mark Roberts, MDWhen we think about the challenges of actually doing clinical trials with these gene therapies, there's a huge development stage in terms of picking the right viral vector with the right surface receptor. That's a major piece of work. That can often take years. The preclinical work is obviously very important as indeed is understanding the natural history because it's really not practical to do placebo-controlled trials of gene therapies.In contrast to other studies, when we turn to phase 1 and phase 2, you'll notice that the patient numbers are often quite small. One is having to think carefully about surrogate measurements of response. Especially when in phase 3 studies, we may be thinking about withdrawing the existing, for example, enzyme replacement therapy because we believe the gene therapy will then be effective.That's just a few snapshots of where we've come and there's a lot more work to be done.In the next part, Dr. Longo will discuss the current treatment landscape and limitations in lysosomal disorders.

Nicola Longo MD, PhD, and Mark Roberts, MDNicola Longo MD, PhDProfessor and Vice Chair of Human Genetics,Allen and Charlotte Ginsburg Chair in Precision Genomic Medicine,Division of Clinical Genetics, Department of Human Genetics,University of California at Los Angeles (UCLA), Los Angeles, CA, USAMark Roberts, MDProfesor and Consultant Neurologist,University of Manchester, Manchester, UKResearch Lead for Adult Metabolic Medicine at Salford Care Organisation, Manchester, UKDrs. Longo and Roberts discuss the current status of gene therapies in rare neuromuscular disorders in this 8-part podcast series. This is derived from the symposium that was presented at World Symposium 2025 in San Diego, California on February 4th-7th 2025 and is intended for healthcare professionals only.This podcast includes information about investigational compounds that do not yet have a regulatory approval or authorization for a specific indication. The safety and efficacy of the agents under investigation have not been established and contents of this podcast shall not be used in any manner to directly or indirectly promote or sell the product for unapproved uses.The views, thoughts, and opinions expressed in this presentation belong solely to the author and are subject to change without notice. The contents of this presentation do not constitute an endorsement of any product or indication by Astellas. In this part, Dr. Roberts will discuss immune responses and other safety concerns related to gene therapies.Mark Roberts, MDUndoubtedly, the immune system is a major issue in these patients. It would be fantastic if we could immunotolerize our patients and indeed prevent the rejection of the therapy. We've talked about the fact that these are viral vectors and of course there may be high seroprevalence of antibodies to these viral vectors, and it's very important in the pre-screening of patients who might be eligible to understand that at the beginning. These of course can have developed over the years and of course can be part of immunological memory and therefore extremely difficult and probably impractical to actually shift.On giving the treatment though as I think we're all aware there is this problem of the innate immunity and potential therefore for acute toxicities and then a learned or adaptive response with cytotoxic T cells and antibodies which may of course become high tighter neutralizing antibodies and potentially antibodies not only against the viral vector, even the functional protein, even the transgene are all theoretical possibilities with time. The capsid, the transgene, and even the protein product can all potentially induce an immunological event. Of course, all of these would lead to both potential patient changes and then a lack of efficacy of the treatment.Indeed, there have been some serious and indeed fatal problems in the gene therapy development program as I think we're all aware. Though many of these are thankfully been overcome. Spinal muscular atrophy has a gene therapy which is licensed, but there were early patients who actually had significant problems. A patient of just 6 months of age who developed kidney failure, two other patients who actually developed liver failure.In Duchenne muscular dystrophy, a very common condition, again there were significant issues and crucially in these patients who all have cardiomyopathy, it was heart failure and cardiac arrest that were big concerns and pulmonary edema and this was seen even with a CRISPR-based technology and is perhaps is best known but has been addressed the excellent myotubular myopathy patients, four patients died and crucially quite a long time after the gene therapy emphasizing the need to monitor these patients extremely carefully and these patients died of cholestatic liver failure albeit that they had a degree of liver dysfunction.That's changed our screening of course of patients, we're now all looking in myotubular patients for liver involvement and Rett syndrome as well. Now these immunoprophylaxis treatment regimes to hopefully try and reduce the immunological reaction against the gene are certainly evolving.This is just a summary of some of the other immunosuppressive regimes used in other disorders, for example, spinal muscular atrophy, but Pompe and MPS as examples of LSDs. Certainly these regimes will continue to evolve and are going to be very important in seeking to make sure that these treatments are effective. It reminds me somewhat of what's happened with enzyme replacement therapy that the use of these immunological strategies in infants has revolutionized the utility of those treatments in early patients.In the next part, Dr. Roberts will discuss lessons learned from gene therapy trials.