Pre-clinical development of AP4B1 gene replacement therapy for hereditary spastic paraplegia type 47

Abstract

Spastic paraplegia 47 (SPG47) is a neurological disorder caused by mutations in the adaptor protein complex 4 β1 subunit (AP4B1) gene leading to AP-4 complex deficiency. SPG47 is characterised by progressive spastic paraplegia, global developmental delay, intellectual disability and epilepsy. Gene therapy aimed at restoring functional AP4B1 protein levels is a rational therapeutic strategy to ameliorate the disease phenotype. Here we report that a single delivery of adeno-associated virus serotype 9 expressing hAP4B1 (AAV9/hAP4B1) into the cisterna magna leads to widespread gene transfer and restoration of various hallmarks of disease, including AP-4 cargo (ATG9A) mislocalisation, calbindin-positive spheroids in the deep cerebellar nuclei, anatomical brain defects and motor dysfunction, in an SPG47 mouse model. Furthermore, AAV9/hAP4B1-based gene therapy demonstrated a restoration of plasma neurofilament light (NfL) levels of treated mice. Encouraged by these preclinical proof-of-concept data, we conducted IND-enabling studies, including immunogenicity and GLP non-human primate (NHP) toxicology studies. Importantly, NHP safety and biodistribution study revealed no significant adverse events associated with the therapeutic intervention. These findings provide evidence of both therapeutic efficacy and safety, establishing a robust basis for the pursuit of an IND application for clinical trials targeting SPG47 patients.

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Item Type:	Article
Authors/Creators:	Wiseman, J.P. Scarrott, J.M. https://orcid.org/0000-0002-6046-7687 Alves-Cruzeiro, J. Saffari, A. https://orcid.org/0000-0003-4119-7519 Böger, C. Karyka, E. https://orcid.org/0000-0001-5551-6109 Dawes, E. Davies, A.K. https://orcid.org/0000-0002-1594-8780 Marchi, P.M. https://orcid.org/0000-0002-8893-3790 Graves, E. Fernandes, F. https://orcid.org/0009-0000-3383-6363 Yang, Z.-L. Coldicott, I. https://orcid.org/0000-0002-1919-7419 Hirst, J. Webster, C.P. https://orcid.org/0000-0003-4197-2036 Highley, J.R. https://orcid.org/0000-0002-4969-6526 Hackett, N. https://orcid.org/0009-0006-9184-4437 Angyal, A. Silva, T.D. Higginbottom, A. https://orcid.org/0000-0002-3246-6695 Shaw, P.J. https://orcid.org/0000-0002-8925-2567 Ferraiuolo, L. Ebrahimi-Fakhari, D. Azzouz, M. https://orcid.org/0000-0001-6564-5967
Copyright, Publisher and Additional Information:	© 2024 The Author(s). Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Creative Commons Public Domain Dedication waiver http://creativecommons.org/publicdomain/zero/1.0/ applies to the data associated with this article, unless otherwise stated in a credit line to the data, but does not extend to the graphical or creative elements of illustrations, charts, or figures. This waiver removes legal barriers to the re-use and mining of research data. According to standard scholarly practice, it is recommended to provide appropriate citation and attribution whenever technically possible.
Keywords:	AAV; AP4B1; Gene Therapy; HSP; SPG47
Dates:	Published: 11 November 2024 Published (online): 2 October 2024 Accepted: 19 September 2024
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine and Population Health
Depositing User:	Symplectic Sheffield
Date Deposited:	16 Oct 2024 09:55
Last Modified:	18 Nov 2024 09:31
Status:	Published
Publisher:	Springer Science and Business Media LLC
Refereed:	Yes
Identification Number:	10.1038/s44321-024-00148-5
Related URLs:	PubMed URL
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:218317

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Pre-clinical development of AP4B1 gene replacement therapy for hereditary spastic paraplegia type 47

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