An Update on Gene Therapy Approaches for Parkinson's Disease: Restoration of Dopaminergic Function.
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ABSTRACT:
SUBMITTER: Van Laar AD
PROVIDER: S-EPMC8543243 | biostudies-literature | 2021
REPOSITORIES: biostudies-literature
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An Update on Gene Therapy Approaches for Parkinson's Disease: Restoration of Dopaminergic Function.
Van Laar Amber D AD Van Laar Victor S VS San Sebastian Waldy W Merola Aristide A Elder J Bradley JB Lonser Russell R RR Bankiewicz Krystof S KS
Journal of Parkinson's disease 20210101 s2
At present there is a significant unmet need for clinically available treatments for Parkinson's disease (PD) patients to stably restore balance to dopamine network function, leaving patients with inadequate management of symptoms as the disease progresses. Gene therapy is an attractive approach to impart a durable effect on neuronal function through introduction of genetic material to reestablish dopamine levels and/or functionally recover dopaminergic signaling by improving neuronal health. On ...[more]
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Project description:Human pluripotent stem cell (hPSC)-based replacement therapy holds great promise in treating Parkinson’s disease (PD). However, the heterogeneity of hPSC-derived donor cells and the low yield of midbrain dopaminergic (mDA) neurons after transplantation hinder its broad clinical application. Here, we depicted the single-cell molecular landscape during mDA neuron differentiation. We found that this process recapitulated the development of multiple but adjacent fetal brain regions including ventral midbrain, isthmus, and ventral hindbrain, resulting in heterogenous donor cell population. We reconstructed the differentiation trajectory of mDA lineage and identified CLSTN2 and PTPRO as specific surface markers of mDA progenitors, which were predictive of mDA neuron differentiation and could facilitate highly enriched mDA neurons (up to 80%) following progenitor sorting and transplantation. Marker sorted progenitors exhibited higher therapeutic potency in correcting motor deficits of PD mice. Different marker sorted grafts had a strikingly consistent cellular composition, in which mDA neurons were enriched, while off-target neuron types were mostly depleted, suggesting stable graft outcomes. Our study provides a better understanding of cellular heterogeneity during mDA neuron differentiation, and establishes a strategy to generate highly purified donor cells to achieve stable and predictable therapeutic outcomes, raising the prospect of hPSC-based PD cell replacement therapies.
2022-06-14 | GSE204796 | GEO
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Project description:IntroductionParkinson's disease (PD) has variable progression; identifying determinants of functional decline in PD is needed for accurate prognostication. Autonomic symptoms can result from dopaminergic therapy but may also independently predict functional decline.MethodsThe sample included individuals with newly diagnosed PD in Parkinson's Progression Markers Initiative. Autonomic symptoms were measured with the Scales-for-Outcomes-in-Parkinson's-Disease-Autonomic (SCOPA-AUT). Presence/absence of autonomic symptoms for SCOPA-AUT total scale and seven subscales was defined, and baseline demographic/clinical data were compared between groups with and without autonomic symptoms. Time-to-functional-dependence, or Schwab-and-England Activities-of-Daily-Living (SE-ADL) ≤70, was compared between groups using hazard models, adjusting for covariates including time-varying levodopa-equivalent daily dosage. If a subscale was associated with a significant subhazard ratio (SHR), hazard models for items in that subscale were generated and gender was evaluated as an effect modifier.Results399 participants were included. Over a median of 72 months (range 6-84), 91 (22.81%) reached SE-ADL ≤70. SCOPA-AUT total/gastrointestinal/urinary/pupillomotor scales were associated with SE-ADL ≤70; respective multivariable SHRs (95% CI, p value) were 1.98 (1.06-3.70, 0.03), 1.71 (1.04-2.81, 0.03), 1.94 (1.25-3.01, <0.01), 2.56 (1.24-5.31, 0.01). Individual items in the gastrointestinal and urinary scales drove associations. Urinary scale associations were seen in males only.ConclusionsSymptoms of gastrointestinal, urinary, pupillomotor dysfunction are associated with functional decline risk in PD, independent of dopaminergic therapy. Detailed assessments of autonomic symptomatology should be utilized in studies attempting to refine predictive models of PD progression.
| S-EPMC9671814 | biostudies-literature