The results support the potential of AAV-Parkin gene therapy as a disease-modifying approach for Parkin-deficient EOPD and developed a translatable gene therapy approach using rodents.
This work generates human induced pluripotent stem cell-derived midbrain dopaminergic neurons using both a 2D differentiation protocol and a recently developed 3D method based on the microencapsulation of hiPSCs in small alginate/fibronectin beads.
A. Zanon, E. Kerschbamer, D. Riekschnitz et al.· Communications Biology· 0 citations
Findings support the protective potential of RTA-408 in SCA3-related models and show its effects were associated with activation of Nrf2-related antioxidant responses, p62 upregulation, and selected improvements in mitochondrial phenotypes.
Shin-Hung Pan, Juichih Chang, Wan-Hsuan Lin et al.· Frontiers in Pharmacology· 0 citations
Mutations in the valosin-containing protein (VCP) gene lead to a hereditary type of inclusion body myositis (hIBM), in which sarcoplasmic and myonuclear inclusions with TAR DNA-binding protein 43 (TDP-43) pathology and mitochondrial abnormalities are observed in histological analysis. Pathophysiological conditions in the cell cause the protein quality control system to depend on the autophagy-lysosome pathway (ALP) for degradation of accumulated misfolded proteins and mitochondrial turnover. BCL2-associated athanogene 3 (BAG3) protein has a role in initiating the ALP. Our aim was to ameliorate disease processes resulting from mitochondrial abnormalities and misfolded protein aggregation by upregulating the ALP through overexpression of human BAG3 (hBAG3). The VCP-A232E mouse, a model for hIBM, received AAVrh74.tMCK.hBAG3 systemically at 3 months of age, and outcome measures, including functional, histological, and molecular studies, were assessed 9 months post-gene delivery. hBAG3 treatment improved treadmill running distance and rotarod duration, reduced the number of TDP-43-positive aggregates, and decreased the number of fibers showing abnormalities in mitochondrial enzyme histochemistry, compared with the untreated cohort. Moreover, hBAG3 gene therapy resulted in improvements in mitophagy and mitochondrial homeostasis observed as increased levels in mitophagy markers Parkin and Bnip3, mitochondria biogenesis marker Pgc1α and mitochondrial DNA-encoded subunits of complex IV, Cox1 and Cox3. In addition, the LC-II/I ratio increased, indicating increased autophagic flux. Our study presents evidence that the strategy of supporting the ALP system by overexpressing BAG3 has potential therapeutic use for myodegenerative conditions associated with abnormal protein aggregates and mitochondrial turnover.
B. Ozes, Lingying Tong, M. Myers et al.· Human Gene Therapy· 0 citations
It is suggested that BL-918 could potentially modulate SMP30 at the functional protein level, and SwissADME and ProTox 3.0 characterized BL-918 as a viable therapeutic lead, outlining key pharmacokinetic targets for future optimization.
Hardi M. Makwana, S. S. Swain, B. Paital et al.· Journal of Applied Pharmaceu...· 0 citations
In vivo proof-of-concept for SNCA-targeted transcriptional repression therapy in a PD-mouse model is provided and its further preclinical development toward investigational new drug enablement is supported.
Bernadette O'Donovan, Joseph E. Rittiner, Suraj Upadhya et al.· Neurotherapeutics· 0 citations
Friedreich ataxia (FA) is a progressive neurodegenerative disorder caused by reduced expression of frataxin (FXN), a mitochondrial protein essential for iron-sulfur (Fe-S) cluster biogenesis. Although gene therapy strategies aimed at restoring FXN have shown promise, excessive expression can lead to mitochondrial dysfunction, emphasizing the importance of maintaining FXN within a physiological range. Here, we evaluated a gene therapy approach based on a human mini-frataxin construct (miniFXN7) incorporating an endogenous regulatory element to enable controlled FXN expression. The construct was delivered systemically using an AAV-PHP.eB vector in the Pvalb-cKO mouse model of FA. MiniFXN7 treatment resulted in widespread neuronal transduction and restoration of FXN expression toward a near-physiological range in the neuronal populations examined. Treated mice exhibited sustained improvements in motor coordination and proprioceptive function, including normalization of H-reflex responses. At the cellular level, miniFXN7 restored succinate dehydrogenase activity, a mitochondrial Fe-S enzyme, and was associated with partial normalization of mitochondrial morphology. In parallel, neuronal integrity was preserved and astrogliosis reduced across the cerebellum. These findings demonstrate that physiologically regulated FXN replacement is sufficient to achieve substantial functional rescue in FA, supporting a gene therapy strategy based on a transgene expression driven by endogenous regulatory elements.
Federica Pilotto, Laure Dall'Agnol, L. Reutenauer et al.· Human Gene Therapy· 0 citations
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