Gene therapies for neurogenetic disorders

Orrin Devinsky¹, Jeff Coller², Rebecca Ahrens-Nicklas³, X Shawn Liu⁴, Nadav Ahituv⁵, Beverly L Davidson⁶, Kathie M Bishop⁷, Yael Weiss⁸, Ana Mingorance⁹

Affiliations

¹ Department of Neurology, NYU Langone Medical Center, New York, NY, USA; Grossman School of Medicine, New York University, New York, NY, USA. Electronic address: od4@nyu.edu.
² Department of Molecular Biology and Genetics, School of Medicine, Johns Hopkins University, Baltimore, MD, USA; Department of Biology, Johns Hopkins University, Baltimore, MD, USA; Johns Hopkins Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA.
³ Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁴ Department of Physiology and Cellular Biophysics, Columbia University Medical Center, Columbia University, New York, NY, USA.
⁵ Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
⁶ Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁷ KMB Consulting, San Diego, CA, USA.
⁸ Mahzi Therapeutics, San Francisco, CA, USA.
⁹ Dracaena Consulting, Madrid, Spain; Loulou Foundation, London, UK; CureSHANK, Beverly Hills, CA, USA. Electronic address: ana@draccon.com.

PMID: 39966070
DOI: 10.1016/j.molmed.2025.01.015

Free article

Review

Gene therapies for neurogenetic disorders

Orrin Devinsky et al. Trends Mol Med. 2025 Sep.

Free article

. 2025 Sep;31(9):814-826.

doi: 10.1016/j.molmed.2025.01.015. Epub 2025 Feb 17.

Authors

Orrin Devinsky¹, Jeff Coller², Rebecca Ahrens-Nicklas³, X Shawn Liu⁴, Nadav Ahituv⁵, Beverly L Davidson⁶, Kathie M Bishop⁷, Yael Weiss⁸, Ana Mingorance⁹

Affiliations

¹ Department of Neurology, NYU Langone Medical Center, New York, NY, USA; Grossman School of Medicine, New York University, New York, NY, USA. Electronic address: od4@nyu.edu.
² Department of Molecular Biology and Genetics, School of Medicine, Johns Hopkins University, Baltimore, MD, USA; Department of Biology, Johns Hopkins University, Baltimore, MD, USA; Johns Hopkins Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA.
³ Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁴ Department of Physiology and Cellular Biophysics, Columbia University Medical Center, Columbia University, New York, NY, USA.
⁵ Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
⁶ Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁷ KMB Consulting, San Diego, CA, USA.
⁸ Mahzi Therapeutics, San Francisco, CA, USA.
⁹ Dracaena Consulting, Madrid, Spain; Loulou Foundation, London, UK; CureSHANK, Beverly Hills, CA, USA. Electronic address: ana@draccon.com.

PMID: 39966070
DOI: 10.1016/j.molmed.2025.01.015

Abstract

Pathogenic variants in over 1700 genes can cause neurogenetic disorders. Monogenetic diseases are ideal targets for genetic therapies; however, the blood-brain barrier (BBB), post-mitotic neurons, and inefficient delivery platforms make gene therapies for neurogenetic diseases challenging. Following nusinersen's 2016 approval, the development of gene therapies for neurogenetic disorders has advanced rapidly, with new delivery vehicles [e.g., BBB-crossing capsids, engineered viral-like proteins, lipid nanoparticles (LNPs)] and novel therapeutic strategies (e.g., regulatory elements, novel RNA therapeutics, tRNA therapies, epigenetic and gene editing). Patient-led disease foundations have accelerated treatment development by addressing trial readiness and supporting translational research. We review the current landscape and future directions in developing gene therapies for neurogenetic disorders.

Keywords: blood–brain barrier; gene regulation; gene therapy; neurological disorders.

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Conflict of interest statement

Declaration of interests O.D. has equity ownership in Regel Therapeutics, Epitor Therapeutics, Actio Bio, Script Therapeutics, Tevard Biosciences, Praxis Precision Therapeutics, and Cirsium Biosciences. He is on the board of Regel Therapeutics, Epitor Therapeutics, Scrtip Therapeutics, and Cirsium Biosciences. He is a Scientific Advisor for all of the aforementioned companies. He has patents relevant to regulatory elements and CRISPR gene editing. J.C. has equity in Tevard Biosciences and patents on tRNA therapeutics. X.S.L. has equity in Epitor Therapeutics and patents on epigenetic editing. Y.W. has equity in and is the CEO of Mahzi Therapeutics. B.L.D. serves on the advisory board of Latus Biosciences, Patch Bio, Spirovant Biosciences, Resilience, and Carbon Biosciences and has sponsored research from Roche, Latus, and Spirovant. A.M. has no conflicts. K.M.B. is an employee of Falcon Bio and a BOD member of Armatus Bio. R.A-N. is an advisor to LatusBio and serves on a Data and Safety Monitoring Board (DSMB) for AskBio.

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Gene therapies for neurogenetic disorders

Affiliations

Gene therapies for neurogenetic disorders

Authors

Affiliations

Abstract

Conflict of interest statement

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LinkOut - more resources

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Medical