It is shown that FMR1 gene therapy using delivery routes and vehicles approved for clinical use improves core phenotypes in a mouse model for FXS, and suggests that a dual route may be needed to achieve full brain coverage.
Abstract
Fragile X Syndrome (FXS) is the most common inherited form of intellectual disability. It is caused by a trinucleotide expansion in the 5' UTR of the Fragile X messenger ribonucleoprotein 1 (FMR1) gene leading to loss of expression of Fragile X messenger ribonucleoprotein (FMRP). There is currently no cure for FXS. We developed an FMR1 gene therapy based on an adeno-associated viral vector designed with strong translational potential for future clinical testing. The viral vector was tested in Fmr1 knockout mice using two translationally relevant delivery routes and ages corresponding to in utero, toddler, and adolescent ages in humans. Functional studies showed that the FMR1 gene therapy improved select translational FXS phenotypes spanning three critical domains: sensory hyperexcitability, adaptation to change, and altered brain activity. Expression after intracerebroventricular injection was most prominent in the forebrain, whereas intravenous delivery predominantly led to expression across midbrain and brainstem, suggesting that a dual route may be needed to achieve full brain coverage. Biodistribution analyses further suggested that FMRP expression must be titrated carefully for optimal rescue. In summary, we show that FMR1 gene therapy using delivery routes and vehicles approved for clinical use improves core phenotypes in a mouse model for FXS.
It is demonstrated that FMRP deficiency drives the aberrant translational upregulation of core m6A writers, a causal relationship definitively validated using CGG-corrected isogenic control lines and suggest a promising avenue for m6A-targeted therapies.
Lu Lu, Avijite Kumer Sarkar, Lan Dao et al.· Molecular Psychiatry· 0 citations
Cockayne Syndrome (CS) is an autosomal recessive, progressive developmental and neurodegenerative disease. Approximately 30% of cases are caused by mutations in the ERCC8/CSA gene. Patients with CS present with cutaneous photosensitivity, growth failure, shorter life span, and a progressive degeneration of the central nervous system. Loss-of-function mutations in CSA result in deficiencies in the transcription-coupled nucleotide excision repair (TC-NER). Currently, no therapies are available for these patients. Adeno-associated virus (AAV)-mediated gene therapy offers an opportunity to address this unmet need. We designed a new AAV vector encoding human CSA under a ubiquitous promoter. We tested the therapeutic efficacy of this AAV9-CSA vector by neonatal intracerebroventicular injection in the Csa-/-;Xpa-/- mouse model. Treatment with AAV9-CSA resulted in a significant increase in lifespan, and broad distribution of human CSA in the brain and heart, without evidence of vector-related toxicity. Despite clear therapeutic benefit, we also observed neuroradiological abnormalities, and neuropathologic alterations, including hypomyelination, astrocytosis, and microgliosis, as well as likely life-limiting transcriptomic alterations in liver at endpoint. Nonetheless, the success of these experiments paves the way for the first clinical translation of an AAV gene therapy for CS patients into humans.
A. R. Batista, Aine C. Scholand, William S. Callahan et al.· Journal of Clinical Investig...· 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
This review evaluates the potential of CRISPR-based editing as a therapeutic strategy for monogenic NDDs and evaluates the limitations that must be addressed before its widespread application in human patients.
Julia Mulles· American Journal of Student...· 0 citations
It is demonstrated that using FUS following systemic administration of an AAV9 vector represents a significant improvement over classical gene therapy protocol for RTT, and the evaluation of the protein levels indicates a possible overdose of Mecp2 protein in the brain cells.
M. Felix, Léna Bourcin, Emilie Borloz et al.· Experimental Neurology· 0 citations
Clinically applicable gene therapy for RTT will likely need to move beyond simple MECP2 replacement and instead rely on precise cell- and dose-dependent regulation of its expression, with an emphasis on non-coding RNA-based and epigenetic mechanisms.
I. Kabdesh, A. Rizvanov, Y. Mukhamedshina· Non-Coding RNA· 0 citations
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