Appendix B

Workshop Agenda

Advancing Gene-Targeted Therapies for
Central Nervous System Disorders: A Workshop

April 23–24, 2019
National Academy of Sciences Building
2101 Constitution Avenue, NW
Washington, DC

Background:

This public workshop will bring together experts and key stakeholders from academia, government, industry, and nonprofit organizations to explore approaches for advancing the development of gene-targeted therapies for central nervous system (CNS) disorders, including approaches that target nucleic acids, such as adeno-associated viruses (AAVs), antisense oligonucleotides (ASOs), and RNA interference, as well as gene product-targeted therapies.

Workshop Objectives:

Invited presentations and discussions will be designed to:

• Provide an overview of the current landscape of gene-targeted therapy approaches for CNS disorders.

• Discuss lessons learned from recent advances in gene therapy and ASO development for retinal dystrophy and spinal muscular atrophy (SMA).
• Compare features of different gene-targeted therapy approaches in development for CNS disorders, and discuss approaches to matching the approach to specific diseases; addressing their respective administration, distribution, and dose challenges; and exploring potential long-term effects.
• Explore clinical development—including biomarker and clinical endpoint selection, trial design to demonstrate disease modification, and the regulatory path—for gene-targeted therapy approaches for rare genetic disorders that have more variable onset and slower progression.
• Discuss what it would take to move beyond rare genetic disorders to develop gene-targeted therapy approaches for more common, heterogeneous disorders such as Alzheimer’s and Parkinson’s diseases.
• Explore opportunities for catalyzing development of gene-targeted therapy approaches for nervous system disorders, including potential collaborative efforts among sectors and across disorders.

April 23, 2019

SESSION I: CURRENT LANDSCAPE AND LESSONS LEARNED

Objectives:

• Provide an overview of the current landscape of gene-targeted therapy approaches for central nervous system disorders.
• Explore lessons learned from gene and ASO therapies that have achieved Food and Drug Administration approval—including translation plans and which animal models were used in preclinical studies, use of dog models for RPE65, role of natural history studies for SMA therapy, and other lessons learned in translation to clinical development.

• Examine lessons learned from gene therapy efforts that were not successful, including neurotrophins for neurodegenerative diseases.

SESSION II: SELECTING GENE-TARGETED THERAPY APPROACHES FOR CNS DISORDERS

Objectives:

• Discuss the promise and potential pitfalls of gene-targeted therapies specifically for CNS disorders.
• For CNS disorders, compare features of different therapies that target nucleic acid, including AAVs, ASOs, and RNA interference, as well as gene product–targeted therapies.

• Explore what makes a CNS disorder potentially amenable to treatment via gene-targeted therapies and how to match therapy modality and mechanism of action to specific diseases.
• Discuss when uncontrolled overexpression is appropriate.

April 24, 2019

SESSION III: GENE-TARGETING THERAPY TECHNOLOGIES FOR CNS DISORDERS

Objectives:

• For different therapy modalities, and with a focus on general issues rather than specific disease indications:
  • Discuss approaches to addressing their respective administration challenges;
  • Explore CNS fluid dynamics and barriers, as well as delivery routes and distribution, and dose; and
  • Examine what is known about clinical and non-clinical safety, as well as potential long-term effects.
• Consider how previously successful approaches for spinal muscular atrophy and retinal dystrophy would need to be adapted for monogenetic disorders that have more variable onset and slower progression, and discuss timing of interventions.
• Discuss what it takes to move beyond monogenetic disorders to develop gene therapy approaches for common, heterogeneous disorders such as Alzheimer’s and Parkinson’s diseases.
• Examine key challenges such as:
  • CNS cell type-specific transduction;
  • Regulation of viral gene expression to optimize safety and efficacy; and
  • Capsid engineering to improve tissue-specific targeting and blood–brain barrier penetration.

SESSION IV: CLINICAL TRIAL DESIGN AND REGULATORY PATHWAYS

Objectives:

• Translation and treatment paradigm: Explore issues with preclinical models, delivery, considerations for first-in-human, immune response, dose–response, and dose and dose regimen selection. What unique challenges do neuropsychiatric diseases present?
• Patient access: Discuss recruitment challenges, natural history studies, and opportunities with registries/patient advocacy.
• Regulatory pathway: Address ethical considerations, issues with standards and harmonization, and overall level of proof required.
• Risk/benefit and value to patients: Consider how to define meaningful, clinically relevant endpoints, and how to demonstrate efficacy, safety, and overall effectiveness over the long run.
  • Specific questions may include: Should long-term toxicity studies be required (6 months or more)? Should biodistribution and rationale be considered for each gene product or can biosimilars be cross-referenced? What is a biosimilar?

SESSION V: MOVING FORWARD

Objectives:

• Discuss new technologies on the horizon, for example, non-viral approaches, small molecules targeting RNA (e.g., ExpansionRx, Arrakis, Skyhawk), chaperones, targeted protein degradation (many companies), and cell penetrant stapled peptide therapeutics (e.g., Fog Pharma).
• How can these approaches be used for psychiatric disorders and other circuit disorders?
• What else do we need to know that we do not know? Examples may include precision medicine for low-incidence disorders, developing a strategic pipeline for treatments, Timothy syndrome, and/or neuregulins.
• Briefly discuss issues related to cost, access, and health equity, as well as AAV manufacturing capacity.