Persistent Expression of Dopamine-Synthesizing Enzymes 15 Years After Gene Transfer in a Primate Model of Parkinson's Disease

Abstract

Restoring dopamine production in the putamen through gene therapy is a straightforward strategy for ameliorating motor symptoms for Parkinson's disease (PD). In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity-based primate model of PD, we previously showed the safety and efficacy of adeno-associated viral (AAV) vector-mediated gene delivery to the putamen of three dopamine-synthesizing enzymes (tyrosine hydroxylase [TH], aromatic l-amino acid decarboxylase [AADC], and guanosine triphosphate cyclohydrolase I [GCH]) up to 10 months postprocedure. Although three of four monkeys in this study have previously undergone postmortem analysis, one monkey was kept alive for 15 years after gene therapy to evaluate long-term effects. Here, we report that this monkey showed behavioral recovery in the right-side limb that remained unchanged for 15 years, at which time euthanasia was carried out owing to onset of senility. Immunohistochemistry of the postmortem brain from this monkey revealed persistent expression of TH, AADC, and GCH genes in the lesioned putamen. Transduced neurons were broadly distributed, with the estimated transduction region occupying 91% of the left postcommissural putamen. No signs of cytotoxicity or Lewy body pathology were observed in the AAV vector-injected putamen. This study provides evidence of long-term safety and efficacy of the triple-transduction method as a gene therapy for PD.

Magnetic resonance imaging–guided phase 1 trial of putaminal AADC gene therapy for Parkinson's disease

“…26 NHP data have shown stable expression for up to 15 years. 27 Open-label data in PD trials must be interpreted with caution given that randomized, blinded, placebocontrolled trials have often failed to replicate findings from open-label trials. Even so, there are key differences between this and other open-label gene therapy trials in PD.…”

Long-Term Delivery of an Anti-SIV Monoclonal Antibody With AAV

“…Both of these reports used periodic induction of expression of an erythropoietin identical in sequence to the monkey's own erythropoietin over 5 or more years of study. Additional examples include the persistent expression of dopamine-synthesizing enzymes in the putamen reported in one monkey for 15 years in a primate model of Parkinson's disease (54); the sustained expression of human α-L-iduronidase, an important enzyme required for the lysosomal degradation of glycosaminoglycans, reported for almost 4 years after intrathecal cervical AAV9 gene delivery in four one-month-old rhesus monkeys (55); the sustained expression of alpha-1 antitrypsin for over 5 years after one AAV vector administration in alpha-1 antitrypsin deficient patients (56); and the successful expression for 3.5 years obtained in two dogs of a dystrophin gene in a canine model for human Duchenne muscular dystrophy using AAV6 and a brief course of immunosuppressants (57), or in a similar study for over 2 years in two dogs using AAV8 in the absence of immunosuppression (58). Remarkably our animal 84-05 never received any immunosuppressant.…”

“…What may be responsible for the absence of ADAs in 84-05 and the continued high level of production of the transgene product over this prolonged period? Factors that have been shown to influence whether, or not, ADAs are observed following AAV-mediated expression of a transgene product include the following: the particular sequence of the transgene product (69); whether the recipient is already making a similar or identical protein (39); the serotype of AAV used (38); and targeted delivery or targeted expression at particular sites or in particular tissues or cells (54,(70)(71)(72)(73)(74)(75)(76). AAV-delivered 5L7 antibody certainly has the potential to be immunogenic in rhesus monkeys since 50% of monkeys receiving it have had robust ADA responses (1).…”

Adeno‐associated virus‐based Alzheimer's disease mouse models and potential new therapeutic avenues

“…Impressively, a recent report showed persistent vector genomes and expression of the therapeutic dopamine-synthesizing enzymes 15 years after AAV delivery to treat the 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP)-lesioned non-human primate (NHP) model of Parkinson's disease (Sehara et al, 2017). These data suggest that AAV-mediated transgene expression in the CNS following a single administration is long-lasting, and possibly lifelong.…”

“…AAV with glial fibrillary acidic protein promoter‐driven ApoE expression was still detectable in the mouse brain at 12 months after injection, while the same construct delivered via an adenovirus ceased expression after 6 weeks (Feng, Eide, Jiang, & Reder, ). Impressively, a recent report showed persistent vector genomes and expression of the therapeutic dopamine‐synthesizing enzymes 15 years after AAV delivery to treat the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐lesioned non‐human primate (NHP) model of Parkinson's disease (Sehara et al, ). These data suggest that AAV‐mediated transgene expression in the CNS following a single administration is long‐lasting, and possibly lifelong.…”