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 Objectives

• Describe current and emerging gene therapy data in lysosomal disorders and its clinical relevance
• Describe role of patients in gene therapy development

Faculty
Shunji Tomatsu, MD, PhD, Professor and Head, Nemours Children’s Health

Alessandra d’Azzo, PhD, Emerita Faculty, Genetics, St. Jude Children’s Research Hospital

Merve Emecen Sanli, MD, Associate Professor, Department of Pediatrics, University of Texas Southwestern Medical Center

Ryan Colburn. Odimm, Inc.

Disclosures
AffinityCE 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, PhD
Dr. D’Azzo has no relevant financial relationships to disclose.

Merve Emecen Sanli, MD
Dr. Sanli has no relevant financial relationships to disclose.

Ryan Colburn
Mr. 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 Relationships
AffinityCE 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 Designation

Physicians
This 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 Assistants
AffinityCE 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.

Nurses
AffinityCE 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 Practitioners
AffinityCE 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 Counselors
AffinityCE 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 Professionals
All other health care professionals comple...

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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 Objectives
Describe 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.

Faculty
Duarte 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 Medicine

Betul Celik, PhD, Postdoctoral Fellow, Nemours Children’s Health

Gregory Newby, PhD, Assistant Professor, Department of Genetic Medicine, Johns Hopkins School of Medicine

Disclosures
AffinityCE 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, PhD
Dr. Raimundo has no relevant financial relationships to disclose.

Betul Celik, PhD
Dr. Celik has no relevant financial relationships to disclose.

Gregory Newby, PhD
Dr. Newby has no relevant financial relationships to disclose.

Mitigation of Relevant Financial Relationships
AffinityCE 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 Designation

Physicians
This 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 Assistants
AffinityCE 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.

Nurses
AffinityCE 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 Practitioners
AffinityCE 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 Counselors
AffinityCE 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 Professionals
All 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 Costs
There is no cost to participate in this activity.

CME Inquiries
For all CME policy-related inquiries, please con...

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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 Objectives

• Describe 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.

Faculty
Oral Alpan, MD, Immunologist, Amerimmune

Svenja Keller, PhD student, University of Zurich

Shoshana Revel-Vilk, MD, PhD, Director, Gaucher Unit & Pediatric Hematology/Oncology Unit, Shaare Zedek Medical Center

Patrick Deegan, MD, Consultant Metabolic Physician, University of Cambridge

Ravi Kamath, MD, PhD, Head of Musculoskeletal Radiology, Inova Health System

Disclosures
AffinityCE 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 Keller
Ms. Keller has no relevant financial relationships to disclose.

Shoshana Revel-Vilk, MD, PhD
Dr. 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, MD
Dr. 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, PhD
Dr. Kamath is on an advisory board for Intrinsic Therapeutics. He is also a consultant for
Sanofi, Takeda, and Spur Therapeutics.

Mitigation of Relevant Financial Relationships
AffinityCE 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 Designation

Physicians
This 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 Assistants
AffinityCE 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.

Nurses
AffinityCE 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 Practitioners
AffinityCE 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 Counselors
AffinityCE 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 Professionals
All other health care professionals completing this continuing education activity will be issued a statement of participation indicating the number of hours of c...

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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 Objectives

• Describe the use of heart organoid models to better understand the pathophysiology of lysosomal disorders and its clinical relevance
• Describe the use and application of brain organoid models in neuropathic Gaucher disease research and treatment

Faculty
Mia 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, PhD
Dr. Horowitz has no relevant financial relationships to disclose.

Aitor Aguirre, PhD
Dr. Aguirre has no relevant financial relationships to disclose.

Ying Sun, PhD
Dr. Sun receives research support from Enkefalos Biosciences and Yuhan Corporation.

Mitigation of Relevant Financial Relationships
AffinityCE 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 Designation

Physicians
This 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 Assistants
AffinityCE 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.

Nurses
AffinityCE 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 Practitioners
AffinityCE 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 Counselors
AffinityCE 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 Professionals
All 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 Costs
There is no cost to participate in this activity.

CME Inquiries
For all CME policy-related inquiries, please contact us at [email protected]
Send customer support requests to [email protected]

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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 Objectives

• Describe recent advances in the use of nanotechnology to treat lysosomal disorders
• Describe the role of nanotechnology in addressing unmet needs in lysosomal disorders
Faculty
Stephan Stern, PhD, DABT
Director of Research and Development, Nanotechnology Characterization Lab (NCL), Frederick National Laboratory for Cancer Research

Ruben Boado, PhD
Professor of Medicine, University of California at Los Angeles

Disclosures
AffinityCE 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, DABT
Dr. Stern has no relevant financial relationships to disclose. 


Ruben Boado, PhD
Dr. Boado has no relevant financial relationships to disclose.

Mitigation of Relevant Financial Relationships
AffinityCE 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 Designation

Physicians
This 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 Assistants
AffinityCE 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.

Nurses
AffinityCE 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 Practitioners
AffinityCE 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 Counselors
AffinityCE 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 Professionals
All 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 Costs
There is no cost to participate in this activity.

CME Inquiries
For all CME policy-related inquiries, please contact us at [email protected]
Send customer support requests to [email protected]

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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 Objectives
Describe recent advances in the applications of AI in lysosomal disorder diagnosis and its clinical relevance

Faculty
Behzad Najafian, MD 
Professor, Department of Laboratory Medicine & Pathology, Department of Medicine, University of Washington

Disclosures
AffinityCE 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, MD
Dr. 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 Relationships
AffinityCE 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 Designation

Physicians
This 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 Assistants
AffinityCE 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.

Nurses
AffinityCE 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 Practitioners
AffinityCE 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 Counselors
AffinityCE 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 Professionals
All 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 Costs
There is no cost to participate in this activity.

CME Inquiries
For all CME policy-related inquiries, please contact us at [email protected]
Send customer support requests to [email protected]

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Alan Beggs, PhD
Director of the Manton Center for Orphan Disease Research
Sir Edwin and Lady Manton Professor of Pediatrics, Boston Children's Hospital
Harvard Medical School, Boston, MA, USA

Julie A. Parsons, MD
Haberfield Endowed Chair in Pediatric Neuromuscular Disorders
Professor of Clinical Pediatrics and Neurology
University of Colorado School of Medicine, Children's Hospital Colorado
Aurora, CO, USA

The 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, MD
As 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.

What are the long-term implications, safety and efficacy of a one-time gene therapy in pediatric patients with neuromuscular diseases?

Alan Beggs, PhD
One 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.

Question
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, MD
Yeah. 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.

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Julie A. Parsons, MD
Haberfield Endowed Chair in Pediatric Neuromuscular Disorders
Professor of Clinical Pediatrics and Neurology
University of Colorado School of Medicine, Children's Hospital Colorado
Aurora, CO, USA

How 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.

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Julie A. Parsons, MD
Haberfield Endowed Chair in Pediatric Neuromuscular Disorders
Professor of Clinical Pediatrics and Neurology
University of Colorado School of Medicine, Children's Hospital Colorado
Aurora, CO, USA

Now, 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.

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