Determining the neuroprotective and neurorestorative efficacy of AAV-hGDF5 in the AAV-α-synuclein rat model of Parkinson’s.
Cure Parkinson's
University College Cork
In Europe, 1.2 million people have Parkinson’s disease (PD), with a total socioeconomic cost of €13.9 billion per annum, which will double by 2030. No current therapy stops the symptoms of PD from worsening. This project proposes that a neurotrophic factor called growth differentiation factor 5 (GDF5) can be applied as a therapeutic to slow or prevent disease deterioration. GDF5 has known neurotrophic effects in preclinical models on midbrain dopaminergic neurons, the cells that degenerate in this disorder. To date, clinical trials of neurotrophic factors have used intracerebral delivery of either glial cell line-derived neurotrophic factor (GDNF) or neurturin (NRTN), but disappointingly, none of the trials have reached their primary end-point and thus are deemed to have failed. GDF5 is distinct from these two neurotrophic factors, in that it acts through a different signalling mechanism. Here the neuroprotective efficacy of an adeno-associated viral vector carrying the GDF5 transgene (AAV-GDF5) will be assessed in the rat α-synuclein model of PD. They will compare the effects of intrastriatal delivery of AAV-GDF5 with those of AAV-GDNF, in the AAV-a-synuclein rat model of PD. They will determine if this molecular therapy can protect dopamine neurons and their axons against a-synuclein-induced degeneration, to maintain brain dopamine levels and improve motor function. In parallel, they will study the protective effects of GDF5 treatment on cultured dopaminergic neurons which have a-synuclein mutations. Specifically, we will evaluate the effects of GDF5 on dopaminergic neuron survival, neurite growth and arborisation, in embryonic rat midbrain primary cultures and in induced pluripotent stem cell (iPSC)-derived dopaminergic neurons carrying SNCA triplication or the A53T mutation, both of which are common mutations in familial cases of PD. Overall, this research will lay the foundation for the translation of GDF5 viral vector therapy to clinic trials for PD.
5.2 Cellular and gene therapies