AAV gene delivery to the spinal cord: serotypes, methods, candidate diseases, and clinical trials

ABSTRACT

Introduction: Adeno-associated viral (AAV) vector-mediated gene delivery to the spinal cord has finally entered the pathway towards regulatory approval. Phase 1 clinical trials using AAV gene therapy for pediatric disorders – spinal muscular atrophy (SMA) and giant axonal neuropathy (GAN) – are now underway.

Areas covered: This review addresses the latest progress in the field of AAV gene delivery to the spinal cord, particularly focusing on the most prominent AAV serotypes and delivery methodologies to the spinal cord. Candidate diseases and scaling up experiments in large animals are also discussed.

Expert opinion: Intravenous (IV) and intrathecal (IT) deliveries seem to undoubtedly be the preferred routes of administration for diffuse spinal cord delivery of therapeutic AAV vectors that can cross the blood-brain barrier (BBB) and correct inherited genetic disorders. Conversely, intraparenchymal delivery is still an undervalued but very viable approach for segmental therapy in afflictions such as ALS or Pompe Disease as a means to prevent respiratory dysfunction.

KEYWORDS:

• AAV vector
• delivery
• direct
• gene therapy
• intramuscular
• intraparenchymal
• intraspinal
• intrathecal
• intravenous
• spinal cord

Article highlights

• AAV vectors are still considered the safest for clinical application in the CNS

• AAV9 can provide widespread and robust transduction in the spinal cord following remote administration

• Intravenous and intrathecal are the routes of choice for systemic delivery of AAV and diffuse gene expression

• Intraparenchymal delivery is a segmental therapy

• Intraparenchymal injections can cover critical segments of the spinal cord involved in disease processes

This box summarizes key points contained in the article.

Declaration of interest

N Boulis has compensated intellectual property rights with Neuralstem, Inc. under an exclusive license from the Cleveland Clinic. He is also a compensated consultant for Neuralstem, MRI Interventions, Agilis Biotherapeutics and Biomedica and has compensated research funding from ALS Association, the Department of Defense, the National Institutes of Health and the Taubman Research Institute. He also has uncompensated stocks with Boston Scientific, Coda Biotherapeutics and Code Runner. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript has not been funded.