In vivo and ex vivo Characterization of a novel spastic paraplegia rescue knockout mouse model to define the therapeutic potential of somatic gene repair in HSP:

Berlin, den 02.06.2020                                        Dr. med. Dr. med. univ. Amir Jahic

Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous group of monogenic disorders in which the main clinical feature is progressive lower limb spasticity. The pathological correlate of HSP is an isolated degeneration of upper motoneuron axons in the central nervous system (CNS). Many of the genes mutated in HSP are poorly characterized; even expressed in organ systems outside the CNS their functional link to axon biology remains unknown. Currently, no causative treatment exists to prevent, retard, or revers progressive disability in patients with HSP.

The main goal of this project is to examine the molecular requirements for therapeutic interventions in HSP. By combining genetic, phenotypical, histopathological, cell biological and biochemical tools with imaging techniques, we attempt to elucidate the molecular mechanism of this disease before and after selective gene repair. Using a novel rescue knockout mouse model as an experimental tool, we will evaluate the potential subcellular abnormalities with the primary focus on endo-lysosomal structures and autophagosomes comparing pre- and postsymptomatic stages. As a whole, the expected results should define the therapeutic potential of somatic gene repair for HSP.