Regulating the mitochondrial permeability transition pore for treating hereditary spastic paraplegia type 7 (SPG7)

Spastic paraplegia 7 (SPG7) is a rare genetic neurological disease, typically with adult onset, characterized by progressive leg weakness and spasticity, besides additional symptoms in the complicated forms, resulting altogether in very poor quality of life. Only symptomatic treatments with muscle relaxant drugs, functional rehabilitation and kinesitherapy, are available.

We propose to search for candidate drugs for SPG7 patients, starting from our recent discovery that mutations of the mitochondrial protein paraplegin causing SPG7 are associated with a defective activity, called flickering, of the mitochondrial permeability transition pore (mPTP).

We demonstrated that SPG7 patient cells and cortical neurons of the Spg7^-/- mouse model have a defect of mPTP flickering, which is restored, together with the in vivo motor dysfunction, by treatment with the benzodiazepine Bz423, a known inducer of mPTP opening that is not an approved drug and exerts unwanted side effects.

Building on this new and original information, we propose conducting a high content screening of EMA/FDA approved drugs to identify active compounds devoid of the Bz423 undesirable activity, but active on flickering. Moreover, the knowledge on the interaction between Bz423 and its mitochondrial target allows a second screening approach based on molecular modeling to identify additional mPTP active molecules from a large library of compounds.

By leveraging the biological assay for mPTP flickering we developed and our in vitro and in vivo models, we will validate  the new drug effectiveness and characterize possible side effects with the prospect of a pilot clinical trial for SPG7 patients.