Gene Therapeutic Strategy for Autosomal Recessive Spastic Paraplegia Arising From Mutations in SPG47 (360G-Wellcome-211506_Z_18_Z)

Hereditary spastic paraplegias (HSPs) are a family of progressive lower-limb spasticity disorders characterized pathologically by degeneration in the corticospinal and spinocerebellar tracts. Spastic paraplegia type 47 (SPG47) is a subtype of HSP, caused by recessive mutations in the AP4B1 gene, leading to a significant reduction in the transcript protein levels. The gene codes for a subunit of Adaptor protein complex 4 (AP4), an essential intracellular trafficking protein in neurones. A loss-of-function hypothesis for SPG47 is backed by substantial emerging evidence, as mutations in all the other subunits of the AP4 complex disrupt the protein's normal and cause a very similar clinical presentation to that of SPG47. Gene therapy aimed at restoring AP4B1 protein expression therefore represents a rational therapeutic approach to ameliorate the disease phenotype. This project aims to design therapeutic vectors (AAV9 and AAV-PHP.B.) to express human AP4B1 gene under Chicken Beta Actin promoter. It also aims to evaluate their in vitro efficacy in cortical neurons isolated from AP4 ß-/- knockout mouse model and AP4B1 KO HeLa cell lines. If successful, the vectors can be tested in the future in animal models and eventually in clinical trials, aiming to treat SGP47 and improving patients’ quality of life.