200. Advancing a State of the Art Gene Therapy for Parkinson's Disease

Abstract

The primary standard of care for Parkinson's disease (PD) is oral dopaminergic treatments and although these are initially highly efficacious, over time they lead to debilitating long term side effects that seriously impact on the quality of life and restrict the long-term effectiveness of such treatments.OXB-102 is a lentiviral-based vector that delivers the genes encoding the three key enzymes in the dopamine (DA) biosynthetic pathway, tyrosine hydroxylase (TH), aromatic L-amino acid decarboxylase (AADC), and GTP-cyclohydrolase (CH1), to nondopaminergic striatal neurons of the sensorimotor putamen, thus providing these cells with the ability to synthesise and release their own DA. The effectiveness of this strategy has already been demonstrated in rodents, non-human primates and Parkinson's (PD) patients (Palfi et. al, Lancet 2014) with a precursor gene therapy vector called ProSavin®. OXB-102 is an improved version of ProSavin® that expresses the same enzymes but with an increased DA production per genetically modified cell.In non-clinical studies the efficacy of a full-strength and a 1/5th dose of OXB-102 has been compared to the efficacy of full-strength ProSavin® in the ‘gold standard’ MPTP NHP model of PD; a vector that does not express any genes was used as a negative control. The longitudinal follow-up consisted of recording clinical rating scores and video-based quantification of locomotor activity before and after vector administration. The full-strength and the 1/5th dose of OXB-102 were as efficacious as the full-strength dose of ProSavin®, whereas the control-treated macaques maintained a significant PD phenotype, indicating improved dopamine production from OXB-102.Positron emission tomography (PET) was also carried out at baseline and at 3 and 6 months following vector administration using 18F-FMT, a presynaptic biomarker that acts as a substrate of AADC. There was a significant increase in the FMT signal in both of the OXB-102 treatment groups that was greater than in the ProSavin® treated animals whilst there was no significant change in the FMT signal in the control treatment group.Results from a 6-month toxicology and biodistribution study in the NHP indicate that the OXB-102 vector is safe and well tolerated following stereotactic administration into the putamen and the vector does not significantly spread beyond the site of administrationGMP manufacture of OXB-102 for a planned clinical trial in PD patients is currently in progress.