*All times listed are in EST


8:00 am Chair’s Opening Remarks

8:05 am Dorsal Root Ganglia Pathology in AAV Preclinical Studies: Meta-Analysis & Mitigation Strategy

  • Juliette Hordeaux Senior Director, Translational Research & Lysosomal Storage Disease, University of Pennsylvania


• The administration of adeno-associated virus (AAV) vectors to nonhuman primates (NHP) can lead to dorsal root ganglion (DRG) pathology
• A meta-analysis including 256 NHP shows that 83% of animals that were administered AAV through the cerebrospinal fluid (CSF), and 32% of those that received an intravenous (IV) injection developed some DRG pathology and secondary axonopathy
• We developed an efficacious mitigation strategy using DRG-specific microRNA targets

8:25 am Dose Optimization for Gene Therapy Using QSP Modeling


Quantitative Systems Pharmacology (QSP) is proving to be an invaluable, especially for novel modalities such as gene therapy and the technology has increasingly been accepted by regulators

A QSP model related the AAV vectors to the affected organ and PK to plasma level to optimize dosing for rare disease gene therapy

The model enabled the simulation of a range of virtual patients, including different ages, ethnicities and body mass


8:35 am Intracisternal AAV9-based Gene Therapy for Lysosomal Storage Diseases: The Clinical Trial Experience


• Intracisternal route of administration in pediatric MPS I and II patients
• Safety and monitoring of intracisternal AAV9 gene therapy
• Biomarker and clinical outcomes assessment challenges in heterogenous phenotypes of MPS II
• Progress and update of the first in human AAV9 gene therapy studies for MPS I and II

8:55 am First-in-Human AAV Gene Therapy for Huntington’s Disease – from Pre-Clinical to the Clinic


AAV5-miRNA gene therapy as potential treatment for Huntington’s disease

miRNA mediated huntingtin lowering in small and large animal models for Huntington’s disease

MRI guided intra-striatal administration of AAV5-miTT in large animals to investigate safety, biodistribution and efficacy in support of a clinical trial


9:25 am Q&A Panel Discussion: Overcoming Toxicity & Immunogenicity Challenges


• Does it depend on the disorder?
• What are best preclinical models for toxicology risk assessment?
• Reviewing preclinical data for CNS and systemic toxicity
• How does this translate into humans?
• Discussing immunogenicity concerns for patients

9:55 am Morning Break

10:30 am Lesson From the Clinic & Why AAV Biology Still Matters


• Following the history of AAV administration for CNS disorders
• Discussing the value of AAV biology
• Reviewing clinical data

10:50 am Safety & Efficacy of Intra-Cisternal Administration of AAV Vectors


• Evaluating the intra-cisternal route: pros and cons
• Exploring preclinical studies of toxicity and biodistribution
• Discussing clinical validation

11:10 am Spinal Subpial Vector Delivery for Treatment of Neurological Disorders in Adult Mammals: Maximizing the Therapeutic Potency While Minimizing Toxicity


• Comparing the potency of AAV vectors in infecting spinal cord and brain neuronal pools after intrathecal vs spinal subpial delivery: adult large animal model(s) experience
• Use of subpial AAV delivery for controlled, segment-targeted transgene expression
• Regional pattern of neurodegenerative changes in specific inherited disease as a denominator defining the required route of treatment vector delivery
• Toxicity of intrathecal vs subpial AAV delivery
• Human subpial injection device: preclinical experience in an adult pig

11:30 am Exploring Advances in Devices for Direct Gene Therapy Injection


• Exploring the state-of-the-art technical improvements for gene therapy delivery
• Introducing the latest MRI-friendly cannulas and needles
• Discussing the common challenges with age of patient, tech transfer and scaling

11:50 am Q&A Panel Discussion: Delivery


• Comparing different patient populations for different indications and their suitability for different delivery routes
• Discussing biodistribution vs invasive procedures for delivery to the brain
• Exploring the risk/benefit of different routes of administration, is the data translatable?
• Introducing technology advances for the delivery devices, where is there room for improvement?


12:10 pm Lunch & Networking

12:40 pm Preclinical Model Selection: Understanding the Biology & the Translatability


• Aspects to consider when selection your preclinical model
• Capsid selection and biological relevance
• Translatability to non-human primates

1:00 pm Quantitative PET Imaging Biodistribution of I-124-labeled Adeno-associated Viral Vectors

  • Ronald Crystal Chairman, Department of Genetic Medicine, Weill Cornell Medicine


• Analyzing the biodistribution of AAV gene transfer vectors following in vivo administration
• Using intravenous and intracisternal routes of administration of AAVrh.10 and AAV9 vectors to nonhuman primates in the absence or presence of anti-capsid immunity, we have identified novel insights into initial capsid biodistribution and organ-specific capsid half-life
• Facilitating quantitative in vivo viral vector dosimetry, which can serve as a technique for evaluation of both on and off-target organ biodistribution, and potentially accelerate gene therapy development through rapid prototyping of novel vector designs

1:20 pm Q&A Panel Discussion: Overcoming Translational Challenges


• Extrapolating dosage data
• Choosing suitable preclinical models
• Seeking translatable biomarkers

1:45 pm Afternoon Break


2:15 pm Clinical Trial Enrolment for Rare Disease Populations & Clinical Endpoints

  • Mark Milton Ophthalmology Therapeutic Area Head, PK Sciences, Novartis


• What level of pre-existing immunity is accepted?
• What level of protein expression is sufficient for different indications?
• What safety biomarkers do you use to understand pathology in man?

2:25 pm Chairs Closing Remarks

2:35 pm Gene Therapy for Spinal Muscular Atrophy: Patient Perspective on Clinical Trials and Impact


• Impact of gene therapy on the SMA patient population
• What really matters? Existing unmet need. How does the risk/benefit ratio differ from developer to patient?
• Informing future gene therapy development and focusing on important metrics

2:55 pm Q&A Panel Discussion: Ethics & Trial Design


• Enrolment criteria for pre-existing immunity titer and how this shifts from company to company
• Forward thinking drug development trial design with the patient in mind
• How has COVID-19 affected gene therapy trials? What can be learned from this for future trial design?

3:30 pm Final Virtual Networking

4:30 pm End of Summit