Gene therapy for CNS disorders: modalities, delivery and translational challenges – Nature.com

Posted: June 24, 2024 at 2:36 am

Marks, P. & Witten, C. Toward a new framework for the development of individualized therapies. Gene Ther. 28, 615617 (2021).

Article CAS PubMed Google Scholar

Kulkarni, J. A. et al. The current landscape of nucleic acid therapeutics. Nat. Nanotechnol. 16, 630643 (2021). This landmark review article comprehensively summarizes biological and technological advancements in four major platforms that accelerated the clinical utility of nucleic acid therapeutics.

Article CAS PubMed Google Scholar

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, 641659 (2018).

Article CAS PubMed Google Scholar

Bulaklak, K. & Gersbach, C. A. The once and future gene therapy. Nat. Commun. 11, 5820 (2020).

Article CAS PubMed PubMed Central Google Scholar

Nance, E., Pun, S. H., Saigal, R. & Sellers, D. L. Drug delivery to the central nervous system. Nat. Rev. Mater. 7, 314331 (2022).

Article CAS PubMed Google Scholar

Ling, Q., Herstine, J. A., Bradbury, A. & Gray, S. J. AAV-based in vivo gene therapy for neurological disorders. Nat. Rev. Drug. Discov. 22, 789806 (2023).

Article CAS PubMed Google Scholar

Terstappen, G. C., Meyer, A. H., Bell, R. D. & Zhang, W. Strategies for delivering therapeutics across the bloodbrain barrier. Nat. Rev. Drug. Discov. 20, 362383 (2021).

Article CAS PubMed Google Scholar

van Haasteren, J., Li, J., Scheideler, O. J., Murthy, N. & Schaffer, D. V. The delivery challenge: fulfilling the promise of therapeutic genome editing. Nat. Biotechnol. 38, 845855 (2020).

Article PubMed Google Scholar

Yin, H. et al. Non-viral vectors for gene-based therapy. Nat. Rev. Genet. 15, 541555 (2014).

Article CAS PubMed Google Scholar

Nbrega, C., Mendona, L. & Matos, C. A. in A Handbook of Gene and Cell Therapy (eds Nbrega, C., Mendona, L. & Matos, C. A.) 117126 (Springer International, 2020).

Lunn, M. R. & Wang, C. H. Spinal muscular atrophy. Lancet 371, 21202133 (2008).

Article PubMed Google Scholar

Mendell, J. R. et al. Five-year extension results of the phase 1 START trial of onasemnogene abeparvovec in spinal muscular atrophy. JAMA Neurol. 78, 834841 (2021). This key paper presents the findings of a clinical trial of Zolgensma a one-time-only gene therapy product used to treat monogenic SMA in paediatric patients.

Article PubMed Google Scholar

Mendell, J. R. et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N. Engl. J. Med. 377, 17131722 (2017).

Article CAS PubMed Google Scholar

Eichler, F. et al. Hematopoietic stem-cell gene therapy for cerebral adrenoleukodystrophy. N. Engl. J. Med. 377, 16301638 (2017).

Article CAS PubMed PubMed Central Google Scholar

Keam, S. J. Eladocagene exuparvovec: first approval. Drugs 82, 14271432 (2022).

CAS PubMed Google Scholar

Rafii, M. S. et al. A phase1 study of stereotactic gene delivery of AAV2-NGF for Alzheimers disease. Alzheimers Dement. 10, 571581 (2014).

Article PubMed Google Scholar

US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT00876863 (2020).

Klein, C. & Schlossmacher, M. G. The genetics of Parkinson disease: implications for neurological care. Nat. Clin. Pract. Neurol. 2, 136146 (2006).

Article CAS PubMed Google Scholar

Trinh, J. & Farrer, M. Advances in the genetics of Parkinson disease. Nat. Rev. Neurol. 9, 445454 (2013).

Article CAS PubMed Google Scholar

Bandres-Ciga, S., Diez-Fairen, M., Kim, J. J. & Singleton, A. B. Genetics of Parkinsons disease: an introspection of its journey towards precision medicine. Neurobiol. Dis. 137, 104782 (2020).

Article CAS PubMed PubMed Central Google Scholar

Xiao, X. et al. APP, PSEN1, and PSEN2 variants in Alzheimers disease: systematic re-evaluation according to ACMG guidelines. Front. Aging Neurosci. 13, 695808 (2021).

Article CAS PubMed PubMed Central Google Scholar

Pilotto, A., Padovani, A. & Borroni, B. Clinical, biological, and imaging features of monogenic Alzheimers disease. BioMed. Res. Int. 2013, e689591 (2013).

Article Google Scholar

Bertram, L. & Tanzi, R. E. Genomic mechanisms in Alzheimers disease. Brain Pathol. 30, 966977 (2020).

Article PubMed PubMed Central Google Scholar

Moore, B. et al. Developing a gene therapy for the treatment of autosomal dominant Alzheimers disease. Hum. Gene Ther. 34, 10491063 (2023).

Article CAS PubMed Google Scholar

Moore, B. D. & Schaeffer, E. Gene replacement of mutant presenilin1 normalizes -secretase function in models of autosomal dominant Alzheimers disease. Alzheimers Dement. 18, e067938 (2022).

Article Google Scholar

US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT00627588 (2013).

Palfi, S. et al. Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinsons disease: a dose escalation, open-label, phase 1/2 trial. Lancet 383, 11381146 (2014).

Article CAS PubMed Google Scholar

Palfi, S. et al. Long-term follow-up of a phase I/II study of prosavin, a lentiviral vector gene therapy for Parkinsons disease. Hum. Gene Ther. Clin. Dev. 29, 148155 (2018).

Article CAS PubMed PubMed Central Google Scholar

Stewart, H. J. et al. Optimizing transgene configuration and protein fusions to maximize dopamine production for the gene therapy of Parkinsons disease. Hum. Gene Ther. Clin. Dev. 27, 100110 (2016).

Article CAS PubMed Google Scholar

Badin, R. A. et al. Gene therapy for Parkinsons disease: preclinical evaluation of optimally configured TH:CH1 fusion for maximal dopamine synthesis. Mol. Ther. Methods Clin. Dev. 14, 206216 (2019).

Article CAS PubMed PubMed Central Google Scholar

US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03720418 (2022).

Bartus, R. T., Weinberg, M. S. & Samulski, R. J. Parkinsons disease gene therapy: success by design meets failure by efficacy. Mol. Ther. 22, 487497 (2014).

Article CAS PubMed PubMed Central Google Scholar

Khan, S. H. Genome-editing technologies: concept, pros, and cons of various genome-editing techniques and bioethical concerns for clinical application. Mol. Ther. Nucleic Acids 16, 326334 (2019).

Article CAS PubMed PubMed Central Google Scholar

Paschon, D. E. et al. Diversifying the structure of zinc finger nucleases for high-precision genome editing. Nat. Commun. 10, 1133 (2019). This study showcases a novel engineered zinc finger architecture possessing 64-fold greater degrees of configuration, enabling it to target any given base with enhanced precision and specificity.

Article PubMed PubMed Central Google Scholar

Miller, J. C. et al. Enhancing gene editing specificity by attenuating DNA cleavage kinetics. Nat. Biotechnol. 37, 945952 (2019).

Article CAS PubMed Google Scholar

Harmatz, P. et al. First-in-human in vivo genome editing via AAVzinc-finger nucleases for mucopolysaccharidosis I/II and hemophilia B. Mol. Ther. 30, 35873600 (2022). This article highlights three in-human clinical studies that successfully and safely employed genome editing for mucopolysaccharidosis I/II and haemophilia B.

Article CAS PubMed PubMed Central Google Scholar

Gillmore, J. D. et al. CRISPRCas9 in vivo gene editing for transthyretin amyloidosis. N. Engl. J. Med. 385, 493502 (2021).

Article CAS PubMed Google Scholar

US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04560790 (2022).

US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04122742 (2024).

US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04601051 (2023).

Heidersbach, A. J., Dorighi, K. M., Gomez, J. A., Jacobi, A. M. & Haley, B. A versatile, high-efficiency platform for CRISPR-based gene activation. Nat. Commun. 14, 902 (2023).

Article CAS PubMed PubMed Central Google Scholar

Casas-Mollano, J. A., Zinselmeier, M. H., Erickson, S. E. & Smanski, M. J. CRISPRCas activators for engineering gene expression in higher eukaryotes. CRISPR J. 3, 350364 (2020).

Article CAS PubMed PubMed Central Google Scholar

Colasante, G. et al. In vivo CRISPRa decreases seizures and rescues cognitive deficits in a rodent model of epilepsy. Brain 143, 891905 (2020). This proof-of-principle study highlights the therapeutic potential of CRISPRa in reducing the incidence of spontaneous seizures in vivo.

Article PubMed PubMed Central Google Scholar

Gupta, R. M. & Musunuru, K. Expanding the genetic editing tool kit: ZFNs, TALENs, and CRISPRCas9. J. Clin. Invest. 124, 41544161 (2014).

Article PubMed PubMed Central Google Scholar

Chauhan, V. P., Sharp, P. A. & Langer, R. Altered DNA repair pathway engagement by engineered CRISPRCas9 nucleases. Proc. Natl Acad. Sci. USA 120, e2300605120 (2023).

Article CAS PubMed PubMed Central Google Scholar

Xue, C. & Greene, E. C. DNA repair pathway choices in CRISPRCas9-mediated genome editing. Trends Genet. 37, 639656 (2021).

Article CAS PubMed PubMed Central Google Scholar

Yang, H. et al. Methods favoring homology-directed repair choice in response to CRISPR/Cas9 induced-double strand breaks. Int. J. Mol. Sci. 21, 6461 (2020).

Article CAS PubMed PubMed Central Google Scholar

Ceccaldi, R., Rondinelli, B. & DAndrea, A. D. Repair pathway choices and consequences at the double-strand break. Trends Cell Biol. 26, 5264 (2016).

Article CAS PubMed Google Scholar

Lieber, M. R. The mechanism of double-strand DNA break repair by the nonhomologous DNA end joining pathway. Annu. Rev. Biochem. 79, 181211 (2010).

Article CAS PubMed PubMed Central Google Scholar

Stinson, B. M. & Loparo, J. J. Repair of DNA double-strand breaks by the non-homologous end joining pathway. Annu. Rev. Biochem. 90, 137164 (2021).

Article CAS PubMed PubMed Central Google Scholar

Davis, A. J. & Chen, D. J. DNA double strand break repair via non-homologous end-joining. Transl. Cancer Res. 2, 130 (2013).

CAS PubMed Google Scholar

Liang, F., Han, M., Romanienko, P. J. & Jasin, M. Homology-directed repair is a major double-strand break repair pathway in mammalian cells. Proc. Natl Acad. Sci. USA 95, 51725177 (1998).

Article CAS PubMed PubMed Central Google Scholar

Wang, H. & Xu, X. Microhomology-mediated end joining: new players join the team. Cell Biosci. 7, 6 (2017).

Article PubMed PubMed Central Google Scholar

Bhargava, R., Onyango, D. O. & Stark, J. M. Regulation of single strand annealing and its role in genome maintenance. Trends Genet. 32, 566575 (2016).

Read the original:
Gene therapy for CNS disorders: modalities, delivery and translational challenges - Nature.com

Related Posts