Gene therapy for CNS disorders: modalities, delivery and translational challenges

Jingjing Gao^{1

2}, Swetharajan Gunasekar³, Ziting Judy Xia³, Kiruba Shalin⁴, Christopher Jiang³, Hao Chen⁵, Dongtak Lee^{3

6}, Sohyung Lee^{3

6}, Nishkal D Pisal⁴, James N Luo^{3

7}, Ana Griciuc^{8

9}, Jeffrey M Karp^{10

11

12

13

14}, Rudolph Tanzi^{15

16}, Nitin Joshi^{17

18}

Affiliations

¹ Department of Biomedical Engineering, University of Massachusetts, Amherst, MA, USA. jgao@umass.edu.
² Center for Bioactive Delivery, Institute for Applied Life Sciences, University of Massachusetts, Amherst, MA, USA. jgao@umass.edu.
³ Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁴ Department of Biomedical Engineering, University of Massachusetts, Amherst, MA, USA.
⁵ Marine College, Shandong University, Weihai, China.
⁶ Harvard Medical School, Boston, MA, USA.
⁷ Department of Surgery, Brigham and Women's Hospital, Boston, MA, USA.
⁸ Harvard Medical School, Boston, MA, USA. agriciuc@mgh.harvard.edu.
⁹ Genetics and Aging Research Unit, McCance Center for Brain Health, Mass General Institute for Neurodegenerative Disease and Department of Neurology, Massachusetts General Hospital, Boston, MA, USA. agriciuc@mgh.harvard.edu.
¹⁰ Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA, USA. jmkarp@bwh.harvard.edu.
¹¹ Harvard Medical School, Boston, MA, USA. jmkarp@bwh.harvard.edu.
¹² Harvard-MIT Program in Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA. jmkarp@bwh.harvard.edu.
¹³ Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA. jmkarp@bwh.harvard.edu.
¹⁴ Broad Institute of MIT and Harvard, Cambridge, MA, USA. jmkarp@bwh.harvard.edu.
¹⁵ Harvard Medical School, Boston, MA, USA. tanzi@helix.mgh.harvard.edu.
¹⁶ Genetics and Aging Research Unit, McCance Center for Brain Health, Mass General Institute for Neurodegenerative Disease and Department of Neurology, Massachusetts General Hospital, Boston, MA, USA. tanzi@helix.mgh.harvard.edu.
¹⁷ Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA, USA. njoshi@bwh.harvard.edu.
¹⁸ Harvard Medical School, Boston, MA, USA. njoshi@bwh.harvard.edu.

PMID: 38898231
DOI: 10.1038/s41583-024-00829-7

Review

Gene therapy for CNS disorders: modalities, delivery and translational challenges

Jingjing Gao et al. Nat Rev Neurosci. 2024 Aug.

. 2024 Aug;25(8):553-572.

doi: 10.1038/s41583-024-00829-7. Epub 2024 Jun 19.

Authors

Affiliations

¹ Department of Biomedical Engineering, University of Massachusetts, Amherst, MA, USA. jgao@umass.edu.
² Center for Bioactive Delivery, Institute for Applied Life Sciences, University of Massachusetts, Amherst, MA, USA. jgao@umass.edu.
³ Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁴ Department of Biomedical Engineering, University of Massachusetts, Amherst, MA, USA.
⁵ Marine College, Shandong University, Weihai, China.
⁶ Harvard Medical School, Boston, MA, USA.
⁷ Department of Surgery, Brigham and Women's Hospital, Boston, MA, USA.
⁸ Harvard Medical School, Boston, MA, USA. agriciuc@mgh.harvard.edu.
⁹ Genetics and Aging Research Unit, McCance Center for Brain Health, Mass General Institute for Neurodegenerative Disease and Department of Neurology, Massachusetts General Hospital, Boston, MA, USA. agriciuc@mgh.harvard.edu.
¹⁰ Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA, USA. jmkarp@bwh.harvard.edu.
¹¹ Harvard Medical School, Boston, MA, USA. jmkarp@bwh.harvard.edu.
¹² Harvard-MIT Program in Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA. jmkarp@bwh.harvard.edu.
¹³ Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA. jmkarp@bwh.harvard.edu.
¹⁴ Broad Institute of MIT and Harvard, Cambridge, MA, USA. jmkarp@bwh.harvard.edu.
¹⁵ Harvard Medical School, Boston, MA, USA. tanzi@helix.mgh.harvard.edu.
¹⁶ Genetics and Aging Research Unit, McCance Center for Brain Health, Mass General Institute for Neurodegenerative Disease and Department of Neurology, Massachusetts General Hospital, Boston, MA, USA. tanzi@helix.mgh.harvard.edu.
¹⁷ Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA, USA. njoshi@bwh.harvard.edu.
¹⁸ Harvard Medical School, Boston, MA, USA. njoshi@bwh.harvard.edu.

PMID: 38898231
DOI: 10.1038/s41583-024-00829-7

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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References

1. Marks, P. & Witten, C. Toward a new framework for the development of individualized therapies. Gene Ther. 28, 615–617 (2021). - PubMed - DOI
1. Kulkarni, J. A. et al. The current landscape of nucleic acid therapeutics. Nat. Nanotechnol. 16, 630–643 (2021). This landmark review article comprehensively summarizes biological and technological advancements in four major platforms that accelerated the clinical utility of nucleic acid therapeutics. - PubMed - DOI
1. Deverman, B. E., Ravina, B. M., Bankiewicz, K. S., Paul, S. M. & Sah, D. W. Y. Gene therapy for neurological disorders: progress and prospects. Nat. Rev. Drug. Discov. 17, 641–659 (2018). - PubMed - DOI
1. Bulaklak, K. & Gersbach, C. A. The once and future gene therapy. Nat. Commun. 11, 5820 (2020). - PubMed - PMC - DOI
1. Nance, E., Pun, S. H., Saigal, R. & Sellers, D. L. Drug delivery to the central nervous system. Nat. Rev. Mater. 7, 314–331 (2022). - PubMed - DOI

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Gene therapy for CNS disorders: modalities, delivery and translational challenges

Affiliations

Gene therapy for CNS disorders: modalities, delivery and translational challenges

Authors

Affiliations

Abstract

References

Publication types

MeSH terms

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Full Text Sources

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Medical

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