Striatal delivery of CERE‐120, an AAV2 vector encoding human neurturin, enhances activity of the dopaminergic nigrostriatal system in aged monkeys

Abstract

Neurturin (NTN) is a potent survival factor for midbrain dopaminergic neurons. CERE-120, an adeno-associated virus type 2 (AAV2) vector encoding human NTN (AAV2-NTN), is currently being developed as a potential therapy for Parkinson's disease. This study examined the bioactivity and safety/tolerability of AAV2-NTN in the aged monkey model of nigrostriatal dopamine insufficiency. Aged rhesus monkeys received unilateral injections of AAV2-NTN into the caudate and putamen, with each animal therefore serving as its own control. Robust expression of NTN within the nigrostriatal system was observed 8 months postadministration. (18)F-fluorodopa imaging using positron emission tomography revealed statistically significant increases in (18)F-fluorodopa uptake in the injected striatum compared with the uninjected side at 4 and 8 months. In addition, at 8 months postadministration, a significant enhancement in tyrosine hydroxylase immunoreactive fibers and an increase in the number of tyrosine hydroxylase immunoreactive cells was observed in the AAV2-NTN injected striatum compared with the uninjected side. Robust activation of phosphorylated extracellular signal-regulated kinase immunoreactivity in the substantia nigra was also observed. Histopathological analyses revealed no adverse effects of AAV2-NTN in the brain. Collectively, these results are consistent with the neurotrophic effects of NTN on the dopaminergic nigrostriatal system and extend the growing body of evidence supporting the concept that AAV2-NTN may have therapeutic benefit for Parkinson's disease.

Neurotrophic factors for the treatment of Parkinson's disease

“…A study using the same expression system in 6-OHDA-lesioned adult rats found long-term neurturin expression in the striatum and dose-dependant protective effects on the nigrostriatal dopaminergic neurones for at least ten months [91]. Similar results were found after application of this system in aged monkeys and no adverse effects were recorded in this study after thorough toxicological testing [93]. A further study by this group found that the expression of neurturin using this system could be sustained for a year in rhesus monkeys, as could its therapeutic effects [94].…”

Protection Against Parkinson’s Disease Progression: Clinical Experience

“…An open-label clinical trial testing a neuroprotective strategy with a gene to synthesize neurturin, an analog of glial-derived neurotrophic factor, is currently underway in 12 subjects. 108 This work is based in part on the positive results of gene therapy studies using recombinant adeno-associated virus carrying a gene for neurturin in monkeys previously exposed to MPTP. 109 Other gene therapy strategies have been proposed from preclinical evidence, based on the potentially neuroprotective activity of several biologically generated substances.…”

Treatment of Parkinson’s Disease with Trophic Factors

“…[47][48][49][50][51][52][53] Evidence for restoration has also been found in rodents treated with 6-OHDA 52 and in aged monkeys, in which there is an age-related loss of dopaminergic phenotype. 54 In the later studies, an adenoassociated type 2 viral vector that encoded for human NRTN was injected unilaterally into the striatum of the aged rhesus monkeys. [ 18 F]Fluorodopa uptake was increased in the NRTN vector-treated striatum, compared with the uninjected side, at 4 and 8 months.…”

“…Postmortem examination also revealed an increase in tyrosine hydroxylase immunoreactivity in the injected striatum, relative to the uninjected side. 54 A number of other trophic factors have a protective effect on dopamine neurons in vitro and in vivo. These other factors are generally less well characterized, but potentially have clinical implications (Table 2).…”

“…The evidence that it is neurorestorative is more limited. 52,54 The NRTN gene (alias NTN) is delivered in serotype 2 adeno-associated virus that specifically targets neurons. The vector is delivered by four stereotaxic injections into each putamen, with two infusions of vector at the inferior and superior part of the putamen.…”