A novel gene therapy approach to reduce neurotoxicity in Parkinson's disease

PROJECT SUMMARY/ABSTRACT Parkinson’s disease (PD) is a common neurodegenerative disorder, with annual societal costs exceeding $52 billion in the US. PD is a complex, multifactorial disease that exhibits a high degree of heterogeneity among affected individuals, who develop several debilitating motor and non-motor symptoms. Current treatments mainly target motor symptoms and cannot slow or stop disease progression. Recent biomarker studies, including two carried out by our team, show PD-specific alterations in kynurenine metabolites that strongly associate with symptom severity, positioning the kynurenine pathway as a potential therapeutic target in PD. The kynurenine pathway produces several metabolites with immunological and neuroactive properties, including quinolinic acid (QUIN), a well-known pro-inflammatory and excitotoxic metabolite. In this project we will conduct pharmacodynamic, pharmacokinetic, and in vivo efficacy studies to aid the development of a novel gene therapy approach aimed at preventing or slowing the progression of neurodegeneration of PD. Our strategy aims to increase the activity of the enzyme aminocarboxy-muconate semialdehyde decarboxylase (ACMSD), a pivotal enzyme that controls QUIN levels. Enhancing ACMSD activity results in a metabolic shift with less QUIN production, whilst producing more of another metabolite, picolinic acid (PIC). Because PIC counteracts QUIN-induced toxicity and can avert oxidative stress through its chelating properties, enhancing ACMSD activity is expected to have a protective effect on the neuronal environment. Our rigorous biomarker studies show PD-alterations corresponding to a compromised ACMSD activity, providing rationale, which is further supported by strong genetic and experimental data. Our preliminary data show that (i) adeno-associated virus (AAV)-mediated overexpression of ACMSD reduces nigral neurodegeneration and neuroinflammation as well as QUIN levels (in cerebrospinal fluid) in a rat model of PD, and (ii) its ablation leads to progressive nigral neurodegeneration in aging mice. In the R61 phase, we will test two AAV-vectors (engineered to target either neurons or glia) side by side, evaluating target engagement and toxicity over time. At the end of this phase, we will identify >1 dose that sustains target engagement (≥20% decrease in QUIN/PIC ratio) before proceeding to the R33 phase. In the R33 phase we will demonstrate that increasing ACMSD activity will mitigate progressive nigral degeneration and behavioral deficits in two rat models of PD (toxin- and α-synuclein-based). Importantly, our studies will be interventional as we will test the effects of AAV-mediated ACMSD overexpression after triggering neuropathology. Altogether, this project will systematically define the parameters required to demonstrate that our approach results in neuroprotection and amelioration of motor deficits in two progressive models of PD-like neurodegeneration, serving as a foundation for future clinical trials.