1062. Functional Rescue of Parkinsonian Non-Human Primates by a Dopamine Producing Multicistronic Lentiviral Vector

Parkinson's disease (PD) is a neurodegenerative disease affecting 1% of the population over 55 years, whose cardinal symptoms include rigidity, resting tremor, bradykinesia and impaired postural reflexes. PD is characterised by a selective loss of dopaminergic neurons in the substantia nigra, creating dopamine deficiency in the target projection area: the striatum. We and others have demonstrated that expression of the dopamine biosynthetic enzymes tyrosine hydroxyalse (TH), aromatic L-amino acid decarboxylase (AADC), and GTP cyclohydrolase 1 (CH1), in the striatum, results in a significant improvement in motor function in animal models of the disease (Azzouz et al., J Neurosci. 2002 22:10302-12; Shen et al., Hum Gene Ther 2000 11:1509-19; Muramatsu et. al., Hum Gene Ther 2002 13:345-354). We have generated an optimised EIAV tricistronic vector LentiVector® (EIAV-TRIC), with an improved expression and safety profile, that can express all the three enzymes in transduced striatal neurons, both in vitro and in vivo. Stereotactic delivery of these vectors in the sensorimotor putamen of MPTP treated macaques with severe parkinsonism, led to significant motor recovery and improvement in clinical rating scales. This was specific to the EIAV-TRIC treated macaques, for similar treatment with a vector expressing a marker gene failed to yield any such improvement. Our results indicate that intraputamenal delivery of dopamine synthesising genes by LentiVector®, can achieve functional rescue in a primate PD model, thus opening the potential for its use in gene therapy of late stage PD patients.