An alternative splicing modulator decreases mutant HTT and improves the molecular fingerprint in Huntington's disease patient neurons

Article Neurosciences

Answer ALS, a large-scale resource for sporadic and familial ALS combining clinical and multi-omics data from induced pluripotent cell lines

Emily G. Baxi et al.

Summary: Answer ALS is a resource that includes patient-derived iPS cell lines, multi-omic data from iPS neurons, and clinical and smartphone data from over 1,000 ALS patients. This data can be used to identify distinct disease subgroups in ALS.

NATURE NEUROSCIENCE (2022)

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Article Multidisciplinary Sciences

An orally available, brain penetrant, small molecule lowers huntingtin levels by enhancing pseudoexon inclusion

Caroline Gubser Keller et al.

Summary: Huntington's Disease is a neurodegenerative disorder caused by CAG repeat expansions in the HTT gene. The orally available and brain penetrant small molecule branaplam lowers HTT transcript by promoting inclusion of a poison exon or pseudoexon.

NATURE COMMUNICATIONS (2022)

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Article Clinical Neurology

Aberrant NOVA1 function disrupts alternative splicing in early stages of amyotrophic lateral sclerosis

Florian Krach et al.

Summary: This study investigates altered alternative splicing (AS) in early stages of amyotrophic lateral sclerosis (ALS) using motor neurons derived from induced pluripotent stem cells. The study finds that RNA-binding proteins NOVA1, NOVA2, and RBFOX2 are present at high levels in insoluble protein fractions and that AS events in ALS-associated motor neurons are enriched for binding sites of these proteins. The study also shows that NOVA1 exhibits increased cytoplasmic protein levels in early stage motor neurons without TDP-43 pathology. Furthermore, the study suggests that additional RNA-binding protein-RNA perturbations occur in parallel to TDP-43 in ALS.

ACTA NEUROPATHOLOGICA (2022)

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Article Clinical Neurology

Huntington's disease-specific mis-splicing unveils key effector genes and altered splicing factors

Ainara Elorza et al.

Summary: Correction of mis-splicing events is a promising therapeutic approach for neurological diseases caused by splicing-affecting mutations. Next-generation RNA sequencing has enabled the investigation of global mis-splicing in diseased tissue to identify key pathogenic mis-spliced genes. Our new intersect-RNA-seq approach captures pathogenic global mis-splicing in the Huntington's disease striatum.

BRAIN (2021)

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Article Biology

Orally administered branaplam does not impact neurogenesis in juvenile mice, rats, and dogs

Diethilde Theil et al.

Summary: The study found that orally administered branaplam has no impact on neurogenesis in juvenile animals, and proposed a new method for assessing developmental neurotoxicity of CNS-active drug candidates in juvenile animal toxicity studies.

BIOLOGY OPEN (2021)

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Article Multidisciplinary Sciences

Regulated control of gene therapies by drug-induced splicing

Alex Mas Monteys et al.

Summary: A universal switch element has been developed for precise control of gene replacement or editing machinery after exposure to small molecules. This switch system, called X-on, allows controlled protein expression by adjusting drug dose, protein stability, and redosing. It offers an opportunity to refine and tailor gene therapies in humans due to its oral bioavailability and safety of the drugs used.

NATURE (2021)

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Review Biochemistry & Molecular Biology