Potential disease-modifying therapies for Huntington's disease: lessons learned and future opportunities

Tabrizi, Sarah J.; Estévez-Fraga, Carlos; Roon‐Mom, Willeke M. C. van; Flower, Michael; Scahill, Rachael I.; Wild, Edward J.; Muñoz-Sanjuán, Ignacio; Sampaio, Cristina; Rosser, Anne; Leavitt, Blair R.

doi:10.1016/s1474-4422(22)00121-1

Cited by 124 publications

(82 citation statements)

References 118 publications

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“…It is worth emphasizing that HD is a genetically caused disease with no known cure. Life-style changes that not only improve the quality of life but also delay disease progression for HD patients are greatly needed ( 90 ). Our study demonstrates the therapeutic potential of chrono-nutrition-based treatment strategies in a pre-clinical model of HD.…”

Section: Discussionmentioning

confidence: 99%

Dietary ketosis improves circadian dysfunction as well as motor symptoms in the BACHD mouse model of Huntington’s disease

et al. 2022

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Disturbances in sleep/wake cycles are common among patients with neurodegenerative diseases including Huntington’s disease (HD) and represent an appealing target for chrono-nutrition-based interventions. In the present work, we sought to determine whether a low-carbohydrate, high-fat diet would ameliorate the symptoms and delay disease progression in the BACHD mouse model of HD. Adult WT and BACHD male mice were fed a normal or a ketogenic diet (KD) for 3 months. The KD evoked a robust rhythm in serum levels of β-hydroxybutyrate and dramatic changes in the microbiome of male WT and BACHD mice. NanoString analysis revealed transcriptional changes driven by the KD in the striatum of both WT and BACHD mice. Disturbances in sleep/wake cycles have been reported in mouse models of HD and are common among HD patients. Having established that the KD had effects on both the WT and mutant mice, we examined its impact on sleep/wake cycles. KD increased daytime sleep and improved the timing of sleep onset, while other sleep parameters were not altered. In addition, KD improved activity rhythms, including rhythmic power, and reduced inappropriate daytime activity and onset variability. Importantly, KD improved motor performance on the rotarod and challenging beam tests. It is worth emphasizing that HD is a genetically caused disease with no known cure. Life-style changes that not only improve the quality of life but also delay disease progression for HD patients are greatly needed. Our study demonstrates the therapeutic potential of diet-based treatment strategies in a pre-clinical model of HD.

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Section: Discussionmentioning

confidence: 99%

Dietary ketosis improves circadian dysfunction as well as motor symptoms in the BACHD mouse model of Huntington’s disease

et al. 2022

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“…Huntington’s disease (HD) is a hereditary neurodegenerative disorder [ 144 ]. Disease-causing genes, also known as Huntington’s genes, produce abnormal Huntington’s proteins which tend to adhere and aggregate, ultimately resulting in neuronal cell death [ 145 , 146 ]. Thus, silencing this gene is a strategy for HD therapy.…”

Section: Research and Applications Of Exosomal Drug Delivery Systems ...mentioning

confidence: 99%

Exosomes as CNS Drug Delivery Tools and Their Applications

et al. 2022

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Central nervous system (CNS) diseases threaten the health of people all over the world. However, due to the structural and functional particularities of the brain and spinal cord, CNS-targeted drug development is rather challenging. Exosomes are small cellular vesicles with lipid bilayers that can be secreted by almost all cells and play important roles in intercellular communication. The advantages of low immunogenicity, the ability to cross the blood-brain barrier, and the flexibility of drug encapsulation make them stand out among CNS drug delivery tools. Herein, we reviewed the research on exosomes in CNS drug delivery over the past decade and outlined the impact of the drug loading mode, administration route, and engineered modification on CNS targeting. Finally, we highlighted the problems and prospects of exosomes as CNS drug delivery tools.

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“…Huntington’s Disease (HD) is a rare autosomal dominant neurodegenerative disease that impairs cognitive and motor function, eventually leading to death ( 1, 2 ). Currently, no disease-modifying treatments are available ( 3 ). HD is caused by an expansion of the CAG repeat tract in the huntingtin gene ( HTT ), with age of disease onset being strongly driven by the number of CAG repeats ( 4-6 ).…”

Section: Introductionmentioning

confidence: 99%

Di-valent siRNA Mediated Silencing of MSH3 Blocks Somatic Repeat Expansion in Mouse Models of Huntington’s Disease

O'Reilly

Belgrad

Ferguson

et al. 2022

Preprint

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Huntington's Disease (HD) is a severe neurodegenerative disorder caused by expansion of the CAG trinucleotide repeat tract in the huntingtin gene. Inheritance of expanded CAG repeats is needed for HD manifestation, but further somatic expansion of the repeat tract in non-dividing cells, particularly striatal neurons, hastens disease onset. Called somatic repeat expansion, this process is mediated by the mismatch repair (MMR) pathway. Among MMR components identified as modifiers of HD onset, MutS Homolog 3 (MSH3) has emerged as a potentially safe and effective target for therapeutic intervention. Here, we identify fully chemically modified short interfering RNA (siRNA) that robustly silence MSH3 in vitro and in vivo. When synthesized in a di-valent scaffold, siRNA-mediated silencing of MSH3 effectively blocked CAG repeat expansion in striatum of two HD mouse models without impacting tumor-associated microsatellite instability. Our findings establish a novel paradigm for treating patients with HD and other repeat expansion diseases.

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Potential disease-modifying therapies for Huntington's disease: lessons learned and future opportunities

Cited by 124 publications

References 118 publications

Dietary ketosis improves circadian dysfunction as well as motor symptoms in the BACHD mouse model of Huntington’s disease

Dietary ketosis improves circadian dysfunction as well as motor symptoms in the BACHD mouse model of Huntington’s disease

Exosomes as CNS Drug Delivery Tools and Their Applications

Di-valent siRNA Mediated Silencing of MSH3 Blocks Somatic Repeat Expansion in Mouse Models of Huntington’s Disease

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