1

Introduction and Overview¹

Therapeutic development for brain disorders is entering its golden age, said Story Landis, co-chair of the Forum on Neuroscience and Nervous System Disorders of the National Academics of Sciences, Engineering, and Medicine. Among the most promising new therapeutic innovations are gene-targeted therapies.

After decades of scientific, clinical, and manufacturing advances, gene-targeted therapies have recently been approved for two rare monogenic neurological disorders: an inherited retinal disease caused by biallelic mutations in the RPE65 gene (known clinically as some types of Leber congenital amaurosis or retinitis pigmentosa) and the progressive and often fatal neuromuscular disorder called spinal muscular atrophy. Gene-targeted therapies for many other neurological disorders are currently in development using several different technologies, said Lamya Shihabuddin, head of the genetic neurologic disease cluster in Sanofi’s rare and neurologic diseases therapeutic area. These approaches include delivery of genes with viral or non-viral vectors, modulating or silencing gene expression with antisense oligonucleotides (ASOs), and other novel technologies on the horizon.

“The beautiful thing about gene therapy is that it makes everything, in theory, druggable,” said Steven Hyman, director of the Stanley Center for

___________________

¹ The planning committee’s role was limited to planning the workshop, and the Proceedings of a Workshop was prepared by the workshop rapporteurs as a factual summary of what occurred at the workshop. Statements, recommendations, and opinions expressed are those of individual presenters and participants; have not been endorsed or verified by the Health and Medicine Division of the National Academies of Sciences, Engineering, and Medicine; and should not be construed as reflecting any group consensus.

Psychiatric Research at the Broad Institute of the Massachusetts Institute of Technology and Harvard University. However, to move gene-targeted therapies from rare monogenic central nervous system (CNS) disorders to more common and complex diseases will require solving many technical challenges, said Shihabuddin. Among the challenges critical for success is robust and efficient delivery of gene-targeted therapies to specific regions of the brain and cell types. Other challenges she mentioned include working with regulators to move from first generation to second generation viral vectors that are safer and more potent, addressing issues of patient access and participation in clinical development, and sharing learnings and data from clinical studies. Addressing these challenges will require creativity and collaboration among academia, industry, research funders, regulators, and patients, said Shihabuddin.

Recognizing the need to bring this broad range of stakeholders together to address these issues, the Forum on Neuroscience and Nervous System Disorders convened a workshop titled Advancing Gene-Targeted Therapies for Central Nervous System Disorders in Washington, DC, on April 23 and 24, 2019.

WORKSHOP OBJECTIVES

The public workshop brought together experts and key stakeholders from academia, government, industry, philanthropic foundations, and disease/patient-focused nonprofit organizations to explore approaches for advancing the development of gene-targeted therapies for CNS disorders, and implications of developing these therapies. Participants explored lessons learned from both successful and unsuccessful clinical development programs; new knowledge about the genetic underpinnings of brain disorders; the current status and future potential of gene-targeted therapies for CNS disorders; challenges and potential solutions for translating preclinical findings to approved therapies; and patient and caregiver perspectives. They also discussed what will be needed to develop these therapies for common disorders such as Alzheimer’s and Parkinson’s diseases, as well as neuropsychiatric and neurodevelopmental disorders such as schizophrenia and autism. The workshop included approaches that target both DNA and RNA, as well as gene products using viral vectors, ASOs, and RNA interference. Box 1-1 presents the full Statement of Task and workshop objectives.

This field is evolving rapidly and the workshop could not cover all research and development under way in this domain, for example, preclinical and early clinical phase work targeting certain CNS disorders, such as forms of blindness other than that caused by biallelic RPE65 mutations, Batten disease, and auditory disorders.

ORGANIZATION OF THE PROCEEDINGS

Chapter 2 describes the current landscape of and lessons learned from the development of gene-targeted therapies for CNS disorders, both approved therapies and those that have failed in clinical trials. Gene-targeted therapy approaches now in development and the challenges they face are explored in Chapter 3. Challenges related to the translation of gene-targeted therapy approaches from preclinical models to approved therapies are discussed in Chapter 4. Chapter 5 explores meaningful engagement of

patients and families, as well as ethical issues related to the development and marketing of gene-targeted therapies, including issues related to data sharing and access. Advancing the development of gene-targeted therapies through further innovation and collaboration is discussed in Chapter 6.