Dopamine Gene therapy for the treatment of Motor and Non-motor symptoms of Parkinson disease. A translational program from Non-Human primate models to patients. – DopaGene

Parkinson’s Disease (PD) is a progressive disorder, commonly characterised by a loss of pigmented neurons within the substantia nigra pars compacta that send axonal projection to the striatum, and in particular the caudate and putamen, resulting in decreased dopamine availability. Clinically, PD is a multisymptomatic neurological disease that includes not only motor symptoms (akinesia, rigidity, tremor) but also non-motor symptoms (psychiatric symptoms such as depression, hypomania and visual hallucinations; cognitive and neuropsychiatric symptoms).
Currently, there is no curative treatment to halt disease progression for PD patients. Therapies include both pharmacologic and surgical approaches but display severe adverse events. Among those, L-DOPA (the metabolic precursor to dopamine) is the most effective symptomatic therapy available and the most commonly prescribed drug for the condition. However, it leads to increase motor fluctuations and dyskinesias.
ProSavin® is a gene therapy approach for PD, which delivers genes encoding the three key enzymes of dopamine biosynthesis pathway to allow long term dopamine replacement in the striatum. Given very encouraging indications of therapeutic benefit for the PD patients combined with an excellent safety profile, evaluation of a higher dose level of ProSavin® would be advantageous before progressing to a randomized sham controlled Phase II study. However, increasing the volume injected per hemisphere is undesirable. A new therapeutic vector (OXB 102), yielding greater levels of dopamine than ProSavin®, has thus been generated. It is currently under investigation in PD primates and shows very encouraging preliminary results with up to 80% motor recovery.
However, we anticipate that, thanks to higher motor recovery in PD patients, oral dopaminergic treatment may be reduced, which will potentially unmask non-motor. It is thus needed to test effects of vector injection in various parts of the striatum on non-motor symptoms.
DopaGene project is an ambitious and innovative translational research program, involving researchers together with clinicians. It aims at i) demonstrating that infusion of the OXB102 vector into the entire striatum or selectively administered in the associative or limbic part of the striatum restores both motor and non-motor dopaminergic symptoms of PD, ii) designing a battery of tests capable of accurately tracking changes in non-motor dopaminergic symptoms over time in Parkinson’s disease patients and iii) validating Dopa specific non motor tests in primates.
DopaGene project results will be used to launch the Phase II clinical trial on motor and non-motor functions. Altogether, DopaGene project will lead to major results which will pave the way for personalized gene therapy in PD patients and will, soon, have strong impacts on quality of life improvement of PD patients and their family. DopaGene project will also ensure French research excellence in PD field and will promote European competitiveness.