A Phase I Study of Aromatic L-Amino Acid Decarboxylase Gene Therapy for Parkinson's Disease

Abstract

Gene transfer of dopamine-synthesizing enzymes into the striatal neurons has led to behavioral recovery in animal models of Parkinson's disease (PD). We evaluated the safety, tolerability, and potential efficacy of adeno-associated virus (AAV) vector-mediated gene delivery of aromatic L-amino acid decarboxylase (AADC) into the putamen of PD patients. Six PD patients were evaluated at baseline and at 6 months, using multiple measures, including the Unified Parkinson's Disease Rating Scale (UPDRS), motor state diaries, and positron emission tomography (PET) with 6-[(18)F]fluoro-L-m-tyrosine (FMT), a tracer for AADC. The short-duration response to levodopa was measured in three patients. The procedure was well tolerated. Six months after surgery, motor functions in the OFF-medication state improved an average of 46% based on the UPDRS scores, without apparent changes in the short-duration response to levodopa. PET revealed a 56% increase in FMT activity, which persisted up to 96 weeks. Our findings provide class IV evidence regarding the safety and efficacy of AADC gene therapy and warrant further evaluation in a randomized, controlled, phase 2 setting.

Neurotransmitter release: vacuolar ATPase V0 sector c-subunits in possible gene or cell therapies for Parkinson’s, Alzheimer’s, and psychiatric diseases

“…ATP6V0C plays a central role in H + transport as one part of the multi-subunit complex of ATPase [30][31][32][33][34][35][36][37][38][39][40][41][42][43][44]. Israel and his group initially proposed that medatophore forms a proteinaceous pore by the six transmemebrane c subunits of ATPase [10,11].…”

“…Although ATP6V0C is expressed in different brain regions (data not shown), ATP6V0C was over-expressed in the mouse brain using adeno-associated virus (AAV) vectors individually harboring cDNAs of rat ATP6V0C [38], reverse form ATP6V0C, and ATP6V0C-GFP [47] Infection with these viruses in the substantia nigra of the intact mouse brain using the microinjection technique [47] revealed ATP6V0C-GFP expression in both tyrosine hydroxylase (TH)-positive neurons and TH-negative cells, which were other non-neuronal cells, probably astrocytes (see Figure. 1 …”

Safety and Tolerability of Magnetic Resonance Imaging-Guided Convection-Enhanced Delivery of AAV2-hAADC with a Novel Delivery Platform in Nonhuman Primate Striatum

“…Intracranial hemorrhage is a common risk of stereotactic craniotomy (Binder et al, 2005) and was also seen in the AAV2-hAADC phase I clinical trial patients with PD (Christine et al, 2009;Muramatsu et al, 2010). Similarly, one of our PBS control animals presented with a possible hemorrhage in the putamen detected only postmortem.…”

“…It was unnecessary to conduct an efficacy study of AAV2-hAADC in NHP because that has been abundantly established (Bankiewicz et al, 2006;Forsayeth et al, 2006;Hadaczek et al, 2010). These data form the basis of a proposed clinical trial of AAV2-hAADC in PD with the recognition that the delivery technique in previous phase I studies (Eberling et al, 2008;Christine et al, 2009;Muramatsu et al, 2010) was unable to ensure sufficient distribution and transgene expression to be able to achieve optimal non-rate-limiting AADC activity in transduced tissue . The experiments in this paper show the safety and tolerability of administering a higher dose of AAV2-hAADC under real-time MR imaging guidance CED in the precommissural striatum of parkinsonian NHP with an optimized clinical cannula.…”

Brain delivery of AAV9 expressing an anti-PrP monovalent antibody delays prion disease in mice

“…Currently, experimental AAV2-based therapies for AD, 28 amyotrophic lateral sclerosis, 29 Huntington's disease 30 and Parkinson disease have been proposed, peaking a phase I clinical trial for Parkinson disease. 31,32 However, the diffusion and transduction efficiency of the AAV2 vectors is limited and could be improved by using the AAV9 serotype as delivery system.…”