Abstract
Gene therapy is emerging as a powerful tool to modulate abnormal gene expression, a hallmark of most CNS disorders. The transformative potentials of recently approved gene therapies for the treatment of spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and active cerebral adrenoleukodystrophy are encouraging further development of this approach. However, most attempts to translate gene therapy to the clinic have failed to make it to market. There is an urgent need not only to tailor the genes that are targeted to the pathology of interest but to also address delivery challenges and thereby maximize the utility of genetic tools. In this Review, we provide an overview of gene therapy modalities for CNS diseases, emphasizing the interconnectedness of different delivery strategies and routes of administration. Important gaps in understanding that could accelerate the clinical translatability of CNS genetic interventions are addressed, and we present lessons learned from failed clinical trials that may guide the future development of gene therapies for the treatment and management of CNS disorders.
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Acknowledgements
The authors thank all authors whose work in CNS gene therapy, drug delivery and related areas contributed to this Review. This work was supported by Alzheimer’s Association (a grant to J.G.), the National Institutes of Health (NIH) grant 1R01AR077718 (to N.J.), and funding from the Department of Anaesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, and Football Players Health Study (funded by a grant from the National Football League Players Association) (to N.J.). The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Medical School, Harvard University or its affiliated academic health-care centres, the National Football League Players Association or the Brigham and Women’s Hospital.
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J.G., S.G., Z.J.X., K.S., C.J., H.C., S.L., N.D.P., A.G., J.M.K., R.T. and N.J. researched data for the article. J.G., S.G., Z.J.X., C.J., H.C., D.L., S.L., N.D.P., J.N.L., A.G., J.M.K., R.T. and N.J. contributed substantially to discussion of the content. J.G., S.G., Z.J.X., K.S. and N.D.P. wrote the article. J.G., S.G., D.L., J.N.L., A.G., J.M.K., R.T. and N.J. reviewed and/or edited the manuscript before submission.
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Competing interests
A.G. and R.T. have issued patents on all forms of gene therapy and immunotherapy for neuroinflammation using CD33 as a target. N.J. and J.M.K. have one pending patent on nanoparticles for gene delivery in the brain.
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Nature Reviews Neuroscience thanks Nicholas D. Mazarakis, Stephanie Schorge and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Glossary
- Adeno-associated viruses
-
(AAVs). Small, non-pathogenic viruses that are used as vectors for delivering genetic material into cells owing to their low immunogenicity and ability to infect both dividing and non-dividing cells.
- Capsid
-
The protein shell that encloses viral genetic materials and facilitates the entry of viral genome to a target cell by binding to receptors on its surface.
- Chemical conjugates
-
A non-viral delivery system formed by covalently attaching a therapeutic agent to another molecule, such as a ligand, polymer scaffold or antibody.
- Convection-enhanced delivery
-
A local delivery method that directly infuses therapeutic agents in the brain through an implanted catheter that generates a pressure gradient at its tip.
- DNA barcodes
-
Short, single-stranded, synthetic DNA oligonucleotides with unique sequences.
- Immunogenicity
-
The ability of a foreign substance, such as a viral or non-viral vector, to provoke an undesirable immune response, which can lead to reduced efficacy of the drug, allergic reactions or other adverse reactions.
- Lentiviral vector
-
One of the most commonly used tools for long-term and stable transgene expression in target cells and tissues owing to their ability to integrate into host genomes.
- microRNA
-
(miRNA). A class of small non-coding RNA molecules, typically around 21–22 nucleotides in length, that play important regulatory roles in gene expression such as gene silencing or repression.
- Monogenic disorders
-
A type of genetic disorder caused by mutation in a single gene, such as Rett syndrome or sickle cell disease.
- mRNA splicing
-
A crucial process that happens during gene transcription and involves the removal of non-coding regions (introns) from the pre-mRNA. The remaining coding regions (exons) join to form the mature RNA molecule.
- Nanoparticles
-
Nanosized particles ranging from 10 to 200 nm that are made of a range of biomaterials including polymers, peptides and lipids.
- Organoids
-
Tiny, self-organized 3D structures composed of cells made in vitro. They recapitulate many aspects of the native tissues and are valuable models for modelling human genetics and disease mechanisms and for drug screening.
- Polygenic diseases
-
Genetic disorders arising from the combined effects of multiple genetic variations.
- Pseudotype
-
A modified version of a virus that is engineered to contain the envelope proteins of a different virus, allowing them to infect cells for which they do not have innate tropism.
- RNA-induced silencing complex
-
(RISC). A multi-protein complex involved in the cell’s gene regulation process. It binds to small interfering RNA (siRNA) or microRNA (miRNA) to form a functional unit to recognize and bind to complementary sequences in the target RNA and exert inhibitory effects, through mRNA degradation or translational repression.
- Serotype
-
A specific strain of a virus, defined by the specific composition or structure of its surface antigens.
- Short hairpin RNA
-
(shRNA). Small non-coding RNA molecules that mimic the structure of microRNA (miRNA) and are effective in gene silencing. They consist of a stem–loop motif that is later processed by cellular enzymes and incorporated into the RNA-induced silencing complex (RISC) to silence complementary mRNA.
- Small interfering RNA
-
(siRNA). Small non-coding RNA molecules around 20–25 nucleotides long, which function by interacting with the RNA-induced silencing complex (RISC) to enable gene silencing.
- Transduction
-
The delivery of genetic materials to cells using viral vectors.
- Transfection
-
The delivery of genetic materials to cells using non-viral methods.
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Gao, J., Gunasekar, S., Xia, Z.(. et al. Gene therapy for CNS disorders: modalities, delivery and translational challenges. Nat. Rev. Neurosci. (2024). https://doi.org/10.1038/s41583-024-00829-7
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DOI: https://doi.org/10.1038/s41583-024-00829-7
