Dataset Information

Gene Therapy for Parkinson's Disease: Preclinical Evaluation of Optimally Configured TH:CH1 Fusion for Maximal Dopamine Synthesis.

ABSTRACT: A recent phase I-II, open-label trial of ProSavin, a lentiviral vector delivering the key enzymes in the dopamine biosynthetic pathway to non-dopaminergic striatal neurons, demonstrated safety and improved motor function in parkinsonian patients. However, the magnitude of the effect suggested that optimal levels of dopamine replacement may not have been achieved. OXB-102, a lentiviral vector with an optimized expression cassette for dopamine biosynthesis, has been shown to achieve a significantly higher dopamine yield than ProSavin. We assessed the efficacy of OXB-102 in the MPTP macaque model of Parkinson's disease (PD). At 6 months post-vector administration, all treated animals showed significant improvements in clinical scores and spontaneous locomotor activity compared to controls, with the highest recovery observed in the OXB-102 high-dose (HD) group. Positron emission tomography quantification of 6-[¹⁸F]-fluoro-L-m-tyrosine uptake showed a significant increase in amino acid decarboxylase activity for all treated animals, compared with controls, where the OXB-102 HD group showed the highest level of dopaminergic activity. A toxicology study in macaques demonstrated that the vector was safe and well tolerated, with no associated clinical or behavioral abnormalities and no immune response mounted against any transgene products. Overall, these data support the further clinical development of OXB-102 for the treatment of PD.

SUBMITTER: Badin RA

PROVIDER: S-EPMC6685641 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Gene Therapy for Parkinson's Disease: Preclinical Evaluation of Optimally Configured TH:CH1 Fusion for Maximal Dopamine Synthesis.

Badin Romina Aron RA Binley Katie K Van Camp Nadja N Jan Caroline C Gourlay Jeanne J Robert Camille C Gipchtein Pauline P Fayard Audrey A Stewart Hannah H Ralph G Scott GS Lad Yatish Y Kelleher Michelle M Loader Julie J Hosomi Koichi K Palfi Stéphane S Mitrophanous Kyriacos A KA Hantraye Philippe P

Molecular therapy. Methods & clinical development 20190716

A recent phase I-II, open-label trial of ProSavin, a lentiviral vector delivering the key enzymes in the dopamine biosynthetic pathway to non-dopaminergic striatal neurons, demonstrated safety and improved motor function in parkinsonian patients. However, the magnitude of the effect suggested that optimal levels of dopamine replacement may not have been achieved. OXB-102, a lentiviral vector with an optimized expression cassette for dopamine biosynthesis, has been shown to achieve a significantl ...[more]

PMID: 31406701

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Project description:PurposeThere is robust evidence that people with schizophrenia show elevated dopamine (DA) synthesis capacity in the striatum. This finding comes from positron emission tomography (PET) studies using radiolabelled l-3,4-dihydroxyphenylalanine (18F-DOPA). DA synthesis capacity also appears to be elevated in the midbrain of people with schizophrenia compared to healthy controls. We therefore aimed to optimise a method to quantify 18F-DOPA uptake in the midbrain of mice, and to utilise this method to quantify DA synthesis capacity in the midbrain of the sub-chronic ketamine model of schizophrenia-relevant hyperdopaminergia.ProceduresAdult male C57Bl6 mice were treated daily with either ketamine (30 mg/kg, i.p.) or vehicle (saline) for 5 days. On day 7, animals were administered 18F-DOPA (i.p.) and scanned in an Inveon PET/CT scanner. Data from the saline-treated group were used to optimise an atlas-based template to position the midbrain region of interest and to determine the analysis parameters which resulted in the greatest intra-group consistency. These parameters were then used to compare midbrain DA synthesis capacity (KiMod) between ketamine- and saline-treated animals.ResultsUsing an atlas-based template to position the 3.7 mm3 midbrain ROI with a T*-Tend window of 15-140 min to estimate KiMod resulted in the lowest intra-group variability and moderate test-retest agreement. Using these parameters, we found that KiMod was elevated in the midbrain of ketamine-treated animals in comparison to saline-treated animals (t(22) = 2.19, p = 0.048). A positive correlation between DA synthesis capacity in the striatum and the midbrain was also evident in the saline-treated animals (r2 = 0.59, p = 0.005) but was absent in ketamine-treated animals (r2 = 0.004, p = 0.83).ConclusionsUsing this optimised method for quantifying 18F-DOPA uptake in the midbrain, we found that elevated striatal DA synthesis capacity in the sub-chronic ketamine model extends to the midbrain. Interestingly, the dysconnectivity between the midbrain and striatum seen in this model is also evident in the clinical population. This model may therefore be ideal for assessing novel compounds which are designed to modulate pre-synaptic DA synthesis capacity.

Dataset Information

Gene Therapy for Parkinson's Disease: Preclinical Evaluation of Optimally Configured TH:CH1 Fusion for Maximal Dopamine Synthesis.

Publications

Gene Therapy for Parkinson's Disease: Preclinical Evaluation of Optimally Configured TH:CH1 Fusion for Maximal Dopamine Synthesis.

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