Gene Therapy in Rare Neurological Diseases

Opening Symposium

Date/Time: Saturday, September 9, 2023 - 5:45 PM – 7:15 PM
Track: Plenary
Room: Salon E (5th Floor)
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Chair: Bryan Traynor, MD, PhD, MMSc, FRCPI, FRCP, FANA

Co-Chair: Beverly L. Davidson, PhD

We have demonstrated that gene modification of a previously untreatable disease, spinobulbar muscular atrophy, is feasible. This session will explore leveraging these advances more broadly to rare neurological disorders. Developing meaningful interventions will require coordination across multiple domains and stakeholders. The session will discuss recent advancements in viral vector and antisense oligonucleotide therapy, including delivery, toxicity, manufacturing, clinical trial design and regulatory issues. This topic is relevant across all subspecialties and perennial interest to neurologists.

Learning Objectives:

  • Describe recent advances in the development of gene and gene-directed therapies.
  • Recognize potential applications of targeted gene therapy for rare neurological diseases.
  • Explain how this new class of medications is revolutionizing clinical research in the neurological field.

Vector-Based Gene Therapies – Advances in Capsids

Speaker: Beverly L. Davidson, PhD

Diseases of the brain are as complex and varied as the many cell types, subcellular types, sub-structures, and complicated connectivity within. As such, it is unlikely that one platform or vector delivery approach can be broadly applied to safely and efficiently treat or attenuate inherited disorders that impact CNS function.  We present a disease-centric approach wherein the most optimal route of delivery for the disease indication is used to identify the most efficient vectors for potential one and done and therapies.  Efforts are made to use routes of delivery that minimize off-target effects, maximize transduction of the target brain regions and target cells within, and retain the ability to transduce similar cell types and regions in cell and rodent models of disease.  Our methods are translatable to a range of CNS indications and aim to improve next generation gene therapies for greater impact to patients.

Optimizing Outcomes in Neurometabolic Disorders with Gene Therapy

Speaker: Rebecca Ahrens-Nicklas, MD, PhD

While individually rare, inborn errors of metabolism (IEMs) affect approximately 1:1,000 individuals.  More than two-thirds of IEMs are characterized by significant neurologic dysfunction, a major source of morbidity and mortality in patients.  Definitive molecular therapies including gene replacement and gene editing strategies are in preclinical and clinical development for several neurometabolic disorders.  IEMs are attractive drug development targets as the molecular defect is known and most disorders have clinically relevant biomarkers.  While some CNS gene therapy programs for IEMs have yielded promising results, many have failed to meet trial endpoints.  Challenges have included achieving adequate distribution in key brain regions, designing safe and well-tolerated vectors, optimizing timing of drug delivery, and selecting meaningful clinical trial endpoints.  Novel strategies to overcome each of these obstacles are needed to maximize the benefit of these potentially transformative therapies.

Antisense Based Therapy for Rare Neurological Diseases

Speaker: C. Frank Bennett, PhD

Currently there are multiple genetic based medicines being pursued for rare neurological diseases including antisense technology, gene therapy and gene editing technologies. Antisense oligonucleotides (ASOs are one of the more advanced technologies. ASOs are synthetic, chemical modified nucleic acid analogs designed to bind to RNA by Watson-Crick base paring. Upon binding to the RNA, ASOs modulate the function of the targeted RNA through a variety of mechanisms. Both protein coding, as well as non-coding RNAs, can be targets of ASO based drugs, significantly broadening therapeutic targets for drug discovery compared to small molecules and protein based therapeutics. The approval of nusinersen (Spinraza™) as a treatment for spinal muscular atrophy (SMA) validates the utility of antisense drugs for the treatment of motor neuron diseases. The application of antisense technology as potential therapy for other rare neurodegenerative diseases and neurodevelopmental disorders will be discussed.

George W. Jacoby Award
Gene Therapy as a Platform: From Giant Axonal Neuropathy to the PaveGT Program

Speaker / Award Recipient: Carsten G. Bönnemann, MD, Habil, FANA

AAV mediated gene replacement therapy carries great promise for rare and ultra rare disease in which the mechanism is loss of function and the cDNA is small enough to fit the packaging capacity of AAV. However, the development of a new AAV gene therapy for every single such rare indication currently is difficult and often prohibitively expensive. At the same time, a predefined vector and expression cassette, administered by the same route, but used with exchangeable transgenes could be used to address biologically and clinically related but genetically distinct disorders - simplifying and shortening the pathway to clinical development by making use of various inherent platforms in such an approach. To illustrate this concept I will discuss the intrathecal gene therapy approach to the childhood neurodegenerative disease Giant Axonal Neuropathy and the Platform Vector Gene Therapy Project of NCATS, NINDS and NHGRI.