Journal Article

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

Azzouz, Mimoun, Angyal, Adrienn, Graves, Emily, Highley, J Robin, Yang, Zih-Liang, Silva, Thushan de, Alves-Cruzeiro, João, Fernandes, Fiona, Hirst, Jennifer, Scarrott, Joseph M, Webster, Christopher P, Shaw, Pamela J, Ebrahimi-Fakhari, Darius, Saffari, Afshin, Karyka, Evangelia, Coldicott, Ian, Wiseman, Jessica P, Ferraiuolo, Laura, Davies, Alexandra K, Hackett, Neil, Higginbottom, Adrian, Marchi, Paolo M, Dawes, Emily, Böger, Cedric

2024

Overview

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. Synopsis Gene replacement therapy using AAV9/hAP4B1 shows promise in treating Spastic paraplegia 47 (SPG47) by restoring AP-4 complex function in an SPG47 mouse model. A single AAV9/hAP4B1 administration into the cerebrospinal fluid (CSF) in postnatal mice restores key disease features, including: ATG9A mislocalization, the presence of calbindin-positive spheroids, brain anatomical defects, and motor dysfunction. Measurement of plasma neurofilament light chain levels was used as a biomarker of effective dosing in postnatal mouse treatment. A single AAV9/hAP4B1 administration into the CSF of adult mice reduces the severity of some key disease features, including: ATG9A mislocalization, the presence of calbindin-positive spheroids, and motor dysfunction. GLP safety and biodistribution studies in non-human primates reveal no significant adverse events, enabling our investigational new drug application to initiat clinical trials in SPG47 patients. Gene replacement therapy using AAV9/hAP4B1 shows promise in treating Spastic paraplegia 47 (SPG47) by restoring AP-4 complex function in an SPG47 mouse model.

• Publisher: Nature Publishing Group UK,Springer Nature
• Subject: AAV / Adaptor Protein Complex 4 - genetics / Adaptor Protein Complex 4 - metabolism / Adaptor Proteins, Vesicular Transport - genetics / Adaptor Proteins, Vesicular Transport - metabolism / Animals / AP4B1 / Biomedical and Life Sciences / Biomedicine / Dependovirus - genetics / Disease Models, Animal / EMBO16 / EMBO27 / Gene Therapy / Genetic Therapy - methods / Genetic Vectors / HSP / Humans / Mice / Molecular Medicine / Spastic Paraplegia, Hereditary - genetics / Spastic Paraplegia, Hereditary - therapy / SPG47