Practical Recommendations for the Selection of Patients for Individualized Splice-Switching ASO-Based Treatments

Human Mutation, Journal Year: 2024, Volume and Issue: 2024, P. 1 - 13

Published: April 18, 2024

Although around 6% of the world's population is affected by rare diseases, only a small number disease-modifying therapies are available. In recent years, antisense oligonucleotides (ASOs) have emerged as one option for development therapeutics orphan diseases. particular, ASOs can be utilized individualized genetic treatments, addressing patients with known disease-causing variant, who would otherwise not able to receive therapy. Careful prioritization variants amenable an ASO approach crucial increase chances successful treatments and reduce costs time drug development. At present, there no consensus on how systematically this selection procedure. Here, we present practical guidelines evaluate standardize process selecting n-of-1 cases. We focus leading loss function in monogenic disorders consider which splice-switching ASO-mediated applicable each case. To ease understanding application our guidelines, created hypothetical transcript covering different pathogenic explained their evaluation detail. support recommendations real-life examples add further considerations applied specific cases provide comprehensive framework eligible variants.

Language: Английский

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A pH-sensitive closed-loop nanomachine to control hyperexcitability at the single neuron level

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: July 4, 2024

Abstract Epilepsy affects 1% of the general population and 30% patients are resistant to antiepileptic drugs. Although optogenetics is an efficient strategy, difficulty illuminating deep brain areas poses translational challenges. Thus, search alternative light sources strongly needed. Here, we develop pH-sensitive inhibitory luminopsin (pHIL), a closed-loop chemo-optogenetic nanomachine composed luciferase-based generator, fluorescent sensor intracellular pH (E 2 GFP), optogenetic actuator (halorhodopsin) for silencing neuronal activity. Stimulated by coelenterazine, pHIL experiences bioluminescence resonance energy transfer between luciferase E GFP which, under conditions acidic pH, activates halorhodopsin. In primary neurons, senses drop associated with hyperactivity optogenetically aborts paroxysmal activity elicited administration convulsants. The expression in hippocampal pyramidal neurons effective decreasing duration increasing latency pilocarpine-induced tonic-clonic seizures upon vivo coelenterazine administration, without affecting higher functions. same treatment markedly seizure manifestations murine model genetic epilepsy. results indicate that represents potentially promising strategy treat drug-refractory

Language: Английский

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Developmental and epileptic encephalopathy 56 due to YWHAG variants: 12 new cases and review of the literature.

European Journal of Paediatric Neurology, Journal Year: 2024, Volume and Issue: 53, P. 63 - 72

Published: Oct. 9, 2024

Language: Английский

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Developmental and Epileptic Encephalopathy: Pathogenesis of Intellectual Disability Beyond Channelopathies

Biomolecules, Journal Year: 2025, Volume and Issue: 15(1), P. 133 - 133

Published: Jan. 15, 2025

Developmental and epileptic encephalopathies (DEEs) are a group of neuropediatric diseases associated with seizures, severe delay or regression psychomotor development, cognitive behavioral deficits. What sets DEEs apart is their complex interplay epilepsy developmental delay, often driven by genetic factors. These two aspects influence one another but can develop independently, creating diagnostic therapeutic challenges. Intellectual disability complicates potential treatment. Pathogenic variants found in 30–50% patients DEE. Many genes mutated encode ion channels, causing current conduction disruptions known as channelopathies. Although channelopathies indeed make up significant proportion DEE cases, many other mechanisms have been identified: impaired neurogenesis, metabolic disorders, disruption dendrite axon growth, maintenance synapse formation abnormalities —synaptopathies. Here, we review recent publications on non-channelopathies an emphasis the linking epileptiform activity intellectual disability. We focus three major describe several recently identified involved pathogenesis

Language: Английский

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Navigating Uncertainty: Assessing Variants of Uncertain Significance in the CDKL5 Gene for Developmental and Epileptic Encephalopathy Using In Silico Prediction Tools and Computational Analysis

Journal of Molecular Neuroscience, Journal Year: 2025, Volume and Issue: 75(1)

Published: Feb. 13, 2025

Language: Английский

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