A new review article summarizes the current state of development, as well as the challenges, of gene therapy approaches for rare diseases of the central nervous system (CNS) such as Friedreich ataxia (FA), spinal muscular atrophy (SMA), and Dravet syndrome.

The review, published in the Journal of Controlled Release, focuses on the need to overcome delivery problems across CNS barriers, and the need for improved tools for safe, monitored, and targeted gene therapy.

“This review should be a concise guide for researchers in studying the evolving landscape of gene therapy for CNS diseases,” the authors wrote. “We offer a list of potential disease candidates for designing new CNS-targeted gene therapies, illustrate the current environment of CNS gene therapies both in the clinic and in human trials, and underscore significant needs in the field in general and for specific diseases.”

Read more about FA experimental therapies

Recent gene therapy developments such as DNA and RNA targeting, base and prime editing, and transcriptional control all offer significant potential over traditional pharmaceutical approaches to CNS disorders, which only offer limited relief given that they do not target the underlying cause of the condition.

However, major challenges to these new therapies persist, including overcoming delivery barriers such as the blood-brain barrier and blood-spinal cord barrier, which impede delivery of molecules to the brain.

A significant advance in crossing these barriers has been achieved with the discovery of adeno-associated virus (AAV) capsids such as rAAV9 and rAAV-PHP, which more efficiently cross the blood-brain barrier. These approaches offer the potential to deliver a functional copy of the mutated gene responsible for a disease, such as the frataxin gene in FA, via the AAV capsid, to the affected cells.

Several prominent issues remain to be resolved in these approaches, including overcoming the immune response (20%-90% of individuals have antibodies against AAVs) and avoiding the high rates of toxicity and adverse events from AAV therapy that have been observed with high AAV doses.


Leong T, Pal A, Cai Q, et al. Clinical gene therapy development for the central nervous system: candidates and challenges for AAVs. J Controlled Release. Published online May 2023. doi:10.1016/j.jconrel.2023.04.009