Brain-Directed AAV Gene Therapy Rescues a Mouse Model of the CLN5 Form of Neuronal Ceroid Lipofuscinosis Disease and Normalizes a Blood Plasma Biomarker of Neurodegeneration | Human Gene Therapy CLN5 disease, caused by mutations in the CLN5 gene, is a form of neuronal ceroid lipofuscinoses (Batten disease). Patients suffer progressive motor dysfunction, vision loss, seizures, and dementia, leading to premature death. Here, we report a preclinical study of AAV9-mediated gene therapy in a Cln5−/− mouse model. Single-dose AAV9 carrying human CLN5 driven by the CAG or human synapsin 1 promoter (hSYN) was administered via intracerebroventricular injection into neonatal and juvenile Cln5−/− mice. Treatment efficacy was evaluated by assessment of neurodegeneration, neuroinflammation, locomotor function, and survival. AAV9 expressing CLN5 driven by the hSYN promoter significantly alleviated neurodegeneration, improved biochemical and glycosphingolipid profiles, neuropathological and locomotor function, and extended lifespan of the Cln5−/− mice. However, gene transfer employing the CAG promoter demonstrated limited therapeutic efficacy. Furthermore, delayed intervention in juveniles provided superior therapeutic response compared with early neonatal intervention and normalized lifespan. Finally, blood plasma neurofilament light that is significantly elevated in the Cln5−/− mice is restored to normal wildtype levels following treatment. These results indicate that brain-directed adeno-associated virus (AAV) gene therapy could be a promising treatment strategy for CLN5 disease and efficacy might be monitored using a noninvasive blood plasma biomarker.

New paper supporting #AAV -mediated #genetherapy for neurodegenerative disease, #CLN5 neuronal ceroid lipofuscinosis. Improved neuropathology, lifespan, locomotor function, biochemistry and normalisation of plasma biomarker. @asgct.bsky.social @bsgct.bsky.social www.liebertpub.com/doi/10.1177/...

Genetic therapies for neurological diseases Often, gene therapy reviews concentrate upon specific therapeutic modalities—particularly either viral vector-mediated or a nonviral approach. Here, we draw together a comprehensive array of knowledge...

New publication covering viral and non-viral genetic therapy for neurological diseases; viral vectors, clinical applications, RNA therapies, antisense oligonucleotides, gene editing and neurosurgery. Great to work on this with titans of neurological genetic therapies research community @ucl.ac.uk

MDFIC2 is a PIEZO channel modulator that can alleviate mechanical allodynia associated with neuropathic pain | PNAS PIEZO channels are mechanical force sensors involved in various biological processes, including somatosensation. To date, only a few PIEZO-binding ...

New publication. Very fortunate to be involved in this study with Amy Geard identifying MDFIC2 as a sensory neuron–enriched modulator of the PIEZO2 mechanosensitive channel. New opportunities for an analgesic target for chronic pain. Well done Habib et al. & James Cox www.pnas.org/doi/10.1073/...

New publication working with lead Tristan McKay studying iPSC models to elucidate new functions for the CLN7 protein and its role in Batten Disease (Neuronal Ceroid Lipofuscinosis). Well done Aseel Sharaireh et al. #BattenDisease #neuroscience #iPSC @natureportfolio.nature.com
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