Recent advancements in gene supplementation therapy are expanding the options for the treatment of neurological disorders. Among the available delivery vehicles, adeno-associated virus (AAV) is often the favoured vector. However, the results have been variable, with some trials dramatically altering the course of disease whereas others have shown negligible efficacy or even unforeseen toxicity. Unlike traditional drug development with small molecules, therapeutic profiles of AAV gene therapies are dependent on both the AAV capsid and the therapeutic transgene. In this rapidly evolving field, numerous clinical trials of gene supplementation for neurological disorders are ongoing. Knowledge is growing about factors that impact the translation of preclinical studies to humans, including the administration route, timing of treatment, immune responses and limitations of available model systems. The field is also developing potential solutions to mitigate adverse effects, including AAV capsid engineering and designs to regulate transgene expression. At the same time, preclinical research is addressing new frontiers of gene supplementation for neurological disorders, with a focus on mitochondrial and neurodevelopmental disorders. In this Review, we describe the current state of AAV-mediated neurological gene supplementation therapy, including critical factors for optimizing the safety and efficacy of treatments, as well as unmet needs in this field.
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S.J.G. has received royalty income from inventions discussed in the article, through licensing agreements with Neurogene, Asklepios Biopharmaceuticals, Taysha Gene Therapies and Abeona Therapeutics. A.B. has received royalty income from inventions discussed in the article from Axovant Gene Therapies and Neurogene. Q.L. has received royalty income from inventions discussed in the article from Taysha Gene Therapies.
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The structural protein surrounding the genome of an encapsulated virus, including adeno-associated viruses (AAVs).
- Convection-enhanced delivery
An experimental gene therapy delivery technique that uses a catheter to insert a thin tube into the brain and applies pressure to deliver the vector.
- Cross-reactive immunological material
(CRIM). Typically refers to the presence of ‘self’ antigens by an individual, such that their immune system is tolerant to those antigens.
A closed circular extrachromosomal DNA molecule formed from a viral genome that serves as a transcription template.
When one copy of a gene is mutated, which leads to loss of function of the protein, only half the amount of functional protein is produced, and that is not enough to support normal cellular functions.
Liver-related adverse effects usually indicated by increased aspartate aminotransferase and alanine aminotransferase levels, sometimes accompanied by thrombocytopenia and coagulopathy.
- Immediate early gene
A gene that is activated rapidly and transiently in response to a wide variety of cellular stimuli, such as neuronal activity.
Within the functional tissue of an organ, which in this Review refers to the brain.
- Kozak sequence
A nucleic acid motif for initiation of translation in vertebrates. The consensus sequence is GCCRCCAUGG, where R is a purine (A or G) and AUG is the initiation codon.
- Open reading frame
A start codon followed by a portion of in-frame DNA sequence that does not include a stop codon.
The upstream element to a gene that can control the timing and cell specificity of expression through the recruitment of transcriptional machinery.
A virus classification based on surface antigen expression and determined by immunological responses in host serum.
Similar to serotype, a viral variant is classified according to surface antigen expression or other characteristics, but is not determined by immunological responses in host serum.
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Ling, Q., Herstine, J.A., Bradbury, A. et al. AAV-based in vivo gene therapy for neurological disorders. Nat Rev Drug Discov 22, 789–806 (2023). https://doi.org/10.1038/s41573-023-00766-7