Delivering a disease-modifying treatment for Huntington's disease

Godinho, Bruno M.D.C.; Malhotra, Meenakshi; O’Driscoll, Caitriona M.; Cryan, John F.

doi:10.1016/j.drudis.2014.09.011

Cited by 42 publications

(27 citation statements)

References 144 publications

(208 reference statements)

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“…The non-allele specific approach has been recently suggested as a valid and safe option that would avoid the time-consuming and costly individualized therapy (40,41). Non-allele specific targeting has been achieved using antisense ONs targeting outside the trinucleotide repeat region and inducing degradation of HTT mRNA via RNase H recruitment (26).…”

Section: Introductionmentioning

confidence: 99%

CTG repeat-targeting oligonucleotides for down-regulating Huntingtin expression

Zaghloul

Gissberg

Moreno

et al. 2017

Nucleic Acids Research

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Huntington's disease (HD) is a fatal, neurodegenerative disorder in which patients suffer from mobility, psychological and cognitive impairments. Existing therapeutics are only symptomatic and do not significantly alter the disease progression or increase life expectancy. HD is caused by expansion of the CAG trinucleotide repeat region in exon 1 of the Huntingtin gene (HTT), leading to the formation of mutant HTT transcripts (muHTT). The toxic gain-of-function of muHTT protein is a major cause of the disease. In addition, it has been suggested that the muHTT transcript contributes to the toxicity. Thus, reduction of both muHTT mRNA and protein levels would ideally be the most useful therapeutic option. We herein present a novel strategy for HD treatment using oligonucleotides (ONs) directly targeting the HTT trinucleotide repeat DNA. A partial, but significant and potentially long-term, HTT knock-down of both mRNA and protein was successfully achieved. Diminished phosphorylation of HTT gene-associated RNA-polymerase II is demonstrated, suggestive of reduced transcription downstream the ON-targeted repeat. Different backbone chemistries were found to have a strong impact on the ON efficiency. We also successfully use different delivery vehicles as well as naked uptake of the ONs, demonstrating versatility and possibly providing insights for in vivo applications.

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Section: Introductionmentioning

confidence: 99%

CTG repeat-targeting oligonucleotides for down-regulating Huntingtin expression

Zaghloul

Gissberg

Moreno

et al. 2017

Nucleic Acids Research

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“…Given that HD is a monogenic disorder, novel approaches aimed at silencing or repairing the mHTT gene, such as antisense oligonucleotides (ASOs), RNA interference (RNAi), ribozymes, DNA enzymes, and genome-editing approaches, are becoming attractive therapeutic options [43]. These strategies directly interfere with the cause of the disease by targeting mHtt at the genomic or post-transcriptional level [44]. Several oligonucleotide-based approaches have been reported as potential allele-selective HD therapeutics [45, 46].…”

Section: Current Therapeutics For Huntington’s Diseasementioning

confidence: 99%

“…Therefore, they represent the most genetically precise model and might be helpful to further investigate genetic factors related to HD pathogenesis [53, 54]. Moreover, gene-silencing technologies based on patient-specific iPSCs may offer a way to correct this monogenic disorder, paving the road for personalized medicine [44, 55, 56]. …”

Section: Modeling Huntington’s Disease In Vitro With Patient-specificmentioning

confidence: 99%

“…However, the HD-iPSC-derived cells still carry the causative mutation which would produce toxic mutant proteins and lead to ultimate cell death. Of note, emerging gene therapies such as RNAi, ASOs, and genome-editing approaches are capable of silencing or repairing the mHTT gene [44]. Therefore, transplantation of the corrected neural cells back into the patient brain would then abate immune rejection, replenish lost cells, and rescue functional deficiencies [56, 75].…”

Section: Pluripotent Stem Cells For Cell Replacement Therapymentioning

confidence: 99%

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Induced Pluripotent Stem Cells in Huntington’s Disease: Disease Modeling and the Potential for Cell-Based Therapy

et al. 2015

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Huntington’s disease (HD) is an incurable neurodegenerative disorder that is characterized by motor dysfunction, cognitive impairment, and behavioral abnormalities. It is an autosomal dominant disorder caused by a CAG repeat expansion in the huntingtin gene, resulting in progressive neuronal loss predominately in the striatum and cortex. Despite the discovery of the causative gene in 1993, the exact mechanisms underlying HD pathogenesis have yet to be elucidated. Treatments that slow or halt the disease process are currently unavailable. Recent advances in induced pluripotent stem cell (iPSC) technologies have transformed our ability to study disease in human neural cells. Here, we firstly review the progress made to model HD in vitro using patient-derived iPSCs, which reveal unique insights into illuminating molecular mechanisms and provide a novel human cell-based platform for drug discovery. We then highlight the promises and challenges for pluripotent stem cells that might be used as a therapeutic source for cell replacement therapy of the lost neurons in HD brains.

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“…Gene therapy approaches have been suggested for the silencing of mutant Htt expression, but they are far from implementation [183]. Another strategy proposed recently is the targeting of Htt cleavage by caspase 6, which gave positive results in a BACHD mouse model [184].…”

Section: Therapeutic Targetingmentioning

confidence: 99%

Genesis of ER stress in Huntington’s Disease

Shenkman

Eiger

Lederkremer

2015

Endoplasmic Reticulum Stress in Diseases

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Recent research has identified ER stress as a major mechanism implicated in cytotoxicity in many neurodegenerative diseases, among them Huntington’s disease. This genetic disorder is of late-onset, progressive and fatal, affecting cognition and movement. There is presently no cure nor any effective therapy for the disease. This review focuses on recent findings that shed light on the mechanisms of the advent and development of ER stress in Huntington’s disease and on its implications, highlighting possible therapeutic avenues that are being or could be explored.

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Delivering a disease-modifying treatment for Huntington's disease

Cited by 42 publications

References 144 publications

CTG repeat-targeting oligonucleotides for down-regulating Huntingtin expression

CTG repeat-targeting oligonucleotides for down-regulating Huntingtin expression

Induced Pluripotent Stem Cells in Huntington’s Disease: Disease Modeling and the Potential for Cell-Based Therapy

Genesis of ER stress in Huntington’s Disease

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