Eight Years of Clinical Improvement in MPTP-Lesioned Primates After Gene Therapy With AAV2-hAADC

Abstract

This study completes the longest known in vivo monitoring of adeno-associated virus (AAV)-mediated gene expression in nonhuman primate (NHP) brain. Although six of the eight parkinsonian NHP originally on study have undergone postmortem analysis, as described previously, we monitored the remaining two animals for a total of 8 years. In this study, NHP received AAV2-human L-amino acid decarboxylase (hAADC) infusions into the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-lesioned putamen. Restoration of AADC activity restored normal response to levodopa and gene expression could be quantitated repeatedly over many years by 6-[(18)F]fluoro-meta-tyrosine (FMT)-positron emission tomography (PET) and confirm that AADC transgene expression remained unchanged at the 8-year point. Behavioral assessments confirmed continued, normalized response to levodopa (improvement by 35% over historical controls). Postmortem analysis showed that, although only 5.6 + or - 1% and 6.6 + or - 1% of neurons within the transduced volumes of the striatum were transduced, this still secured robust clinical improvement. Importantly, there were no signs of neuroinflammation or reactive gliosis at the 8-year point, indicative of the safety of this treatment. The present data suggest that the improvement in the L-3,4-dihydroxyphenylalanine (L-Dopa) therapeutic window brought about by AADC gene therapy is pronounced and persistent for many years.

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

“…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 .…”

“…CED is a pressurized parenchymal infusion technique that allows therapeutic agents to be distributed throughout large volumes of brain (Bobo et al, 1994). CED of AAV2-hAADC results in robust, essentially permanent, gene expression in the striatum and its beneficial effect has been demonstrated in several preclinical studies in rodent and nonhuman primate (NHP) models of PD (Bankiewicz et al, 2000(Bankiewicz et al, , 2006SanchezPernaute et al, 2001;Forsayeth et al, 2006;Hadaczek et al, 2010). These preclinical studies led to a phase I clinical trial in patients with PD (Eberling et al, 2008;Christine et al, 2009;Valles et al, 2010), in which two cohorts of patients with moderately advanced PD received a bilateral infusion of either a low or high dose of AAV2-hAADC vector into the putamen.…”

Recent Advances in RNA Interference Therapeutics for CNS Diseases

“…Thus, indwelling ports for brain access will be required. However, expression of transgenes after AAV delivery has been observed to last many years (>8 years) in the primate brain [60]. Whether these same platforms can provide for lasting expression of RNAi triggers sufficient to last the life of the patient, or at the least, many years, is not yet known.…”

“…In general, AAVs are non-pathogenic and have low immunogenic properties, which make them ideal for gene delivery in vivo [38]. AAVs confer robust expression, efficiently transduce neurons and other cell types, and, in the absence of an immune response to what is being expressed, can afford long-term expression [59][60][61].…”

Gene Therapy for the Nervous System: Challenges and New Strategies

“…Two other clinical trials have tested AAV vectors carrying mammalian promoters such as the mouse phosphoglycerate kinase (PGK) promoter [120], or the rat neuron-specific enolase (NSE) promoter [121]. The choice of promoters is based on the availability of extensive data from pre-clinical studies in different animal models showing that AAV-mediated transgene expression under these promoters is stable and long lasting in the mammalian brain [122][123][124][125][126][127]. The stability of AAV gene expression in the human brain has been evaluated in clinical trials using an AAV2 vector encoding aromatic amino acid decarboxylase (AADC) injected into the putamen of Parkinson's disease patients [116], or children afflicted with AADC deficiency [115].…”