Pre-clinical development of AP4B1 gene replacement therapy for hereditary spastic paraplegia type 47
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.
Authors
- Neil R. Hackett (ORCID: https://orcid.org/0009-0006-9184-4437)
- Evangelia Karyka (ORCID: https://orcid.org/0000-0001-5551-6109)
- Emily Graves (ORCID: https://orcid.org/0000-0003-1697-5227)
- Christopher P Webster (ORCID: https://orcid.org/0000-0003-4197-2036)
- Joseph M. Scarrott (ORCID: https://orcid.org/0000-0002-6046-7687)
- J. Robin Highley (ORCID: https://orcid.org/0000-0002-4969-6526)
- Laura Ferraiuolo (ORCID: https://orcid.org/0000-0001-9118-5714)
- Zih-Liang Yang (ORCID: https://orcid.org/0000-0002-9792-0799)
- Darius Ebrahimi‐Fakhari (ORCID: https://orcid.org/0000-0002-0026-4714)
- Mimoun Azzouz (ORCID: https://orcid.org/0000-0001-6564-5967)
- João Alves-Cruzeiro
- Paolo Marchi (ORCID: https://orcid.org/0000-0002-8893-3790)
- Thushan I. de Silva (ORCID: https://orcid.org/0000-0002-6498-9212)
- Alexandra K. Davies (ORCID: https://orcid.org/0000-0002-1594-8780)
- Jessica Wiseman
- Afshin Saffari (ORCID: https://orcid.org/0000-0003-4119-7519)
- Jennifer Hirst (ORCID: https://orcid.org/0000-0001-9063-8494)
- Ian Coldicott (ORCID: https://orcid.org/0000-0002-1919-7419)
- Pamela J. Shaw (ORCID: https://orcid.org/0000-0002-8925-2567)
- Cedric Böger
- Emily Dawes
- Adrian Higginbottom
- Adrienn Angyal
- Fiona Fernandes
Institutions
- Boston Children's Hospital (US)
- Harvard University (US)
- Heidelberg University (DE)
- University of Cambridge (GB)
- Manchester Academic Health Science Centre (GB)
- University Hospital Heidelberg (DE)
- University of Manchester (GB)
- Sheffield Teaching Hospitals NHS Foundation Trust (GB)
- Addenbrooke's Hospital (GB)
- University of Sheffield (GB)
Publication Details
- Journal
- EMBO Molecular Medicine
- Published
- 2024-10-02
- DOI
- https://doi.org/10.1038/s44321-024-00148-5
- Citations
- 11
- Primary Topic
- Hereditary Neurological Disorders
- Type
- article
- Field-Weighted Citation Impact
- 2.95
Funders
- LifeArc
- Spastic Paraplegia Foundation
- Innovative Health Initiative
- Alzheimer’s Research UK
- Medical Research Council
- European Research Council
- NIHR Sheffield Biomedical Research Centre
- National Institute of Neurological Disorders and Stroke