CRISPR/Cas9-mediated gene editing ameliorates neurotoxicity in mouse model of Huntington’s disease

Su, Yang; Chang, Ronald; Yang, Huiming; Zhao, Ting; Hong, Yuling; Kong, Ha Eun; Sun, Xiaobo; Qin, Zhaohui S.; Jin, Peng; Li, Shihua; Li, Shengbo Eben

doi:10.1172/jci92087

Cited by 317 publications

(268 citation statements)

References 21 publications

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“…This resulted in permanent and mutant allele‐specific inactivation of the mHTT gene . Recently the method was successfully tested in an HD rodent model . This affirms the feasibility of this approach but much preclinical work is needed to bring these rapidly evolving technologies to the clinic, especially given recent concerns about unexpected off‐target mutations with CRISPR/Cas9 gene editing .…”

Section: Biomarkersmentioning

confidence: 83%

Huntington's disease: a clinical review

McColgan

Tabrizi

2017

Euro J of Neurology

786

645

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Huntington's disease (HD) is a fully penetrant neurodegenerative disease caused by a dominantly inherited CAG trinucleotide repeat expansion in the huntingtin gene on chromosome 4. In Western populations HD has a prevalence of 10.6–13.7 individuals per 100 000. It is characterized by cognitive, motor and psychiatric disturbance. At the cellular level mutant huntingtin results in neuronal dysfunction and death through a number of mechanisms, including disruption of proteostasis, transcription and mitochondrial function and direct toxicity of the mutant protein. Early macroscopic changes are seen in the striatum with involvement of the cortex as the disease progresses. There are currently no disease modifying treatments; therefore supportive and symptomatic management is the mainstay of treatment. In recent years there have been significant advances in understanding both the cellular pathology and the macroscopic structural brain changes that occur as the disease progresses. In the last decade there has been a large growth in potential therapeutic targets and clinical trials. Perhaps the most promising of these are the emerging therapies aimed at lowering levels of mutant huntingtin. Antisense oligonucleotide therapy is one such approach with clinical trials currently under way. This may bring us one step closer to treating and potentially preventing this devastating condition.

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Section: Biomarkersmentioning

confidence: 83%

Huntington's disease: a clinical review

McColgan

Tabrizi

2017

Euro J of Neurology

786

645

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“…Indeed, reducing or suppressing HTT production was shown to block disease progression and reverse disease phenotypes in animal models. 5,6 Several HTT-lowering therapies including antisense oligonucleotides (ASOs) have demonstrated great potential for HD treatment.…”

Section: Introductionmentioning

confidence: 99%

Mesenchymal stem cells alleviate AQP-4-dependent glymphatic dysfunction and improve brain distribution of antisense oligonucleotides in BACHD mice

Feng

et al. 2019

Stem Cells

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Huntington's disease (HD) is a neurodegenerative disorder caused by a mutation in the huntingtin (HTT) gene that results in the production of neurotoxic mutant HTT (mHTT) protein. Suppressing HTT production with antisense oligonucleotides (ASOs) is a promising treatment strategy for HD; however, the difficulty of delivering ASOs to deep brain structures is a major barrier for its clinical application. The glymphatic system of astrocytes involving aquaporin 4 (AQP-4) controls the entry of macromolecules from the cerebrospinal fluid into the brain. Mesenchymal stem cells (MSCs) target astrocytes to inhibit neuroinflammation. Here we examined the glymphatic distribution of ASO in the brain and the therapeutic potential of combining intravenously injection of mesenchymal stem cells (IV-MSC) and ASOs for the treatment of HD. Our results show that Cy3-labeled ASOs entered the brain parenchyma via the perivascular space following cisternal injection, but the brain distribution was significantly lower in AQP-4 −/− as compared with wild-type mice. Downregulation of the AQP-4 M23 isoform was accompanied by decreased brain levels of ASOs in BACHD mice as well as an increase in astrogliosis and phosphorylation of nuclear factor κB (NF-κB) p65. IV-MSC treatment restored AQP-4 M23 expression, attenuated astrogliosis, and decreased NF-κB p65 phosphorylation; it also increased the brain distribution of ASOs and enhanced the suppression of mHTT in BACHD mice.These results suggest that modulating glymphatic activity using IV-MSC is a novel strategy for improving the potency of ASO in the treatment of HD.Teng-teng Wu and Feng-juan Su have contributed equally to this work.

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“…For example, a recent report on using CRISPR/Cas9-mediated gene editing has successfully ameliorated neurotoxicity and alleviated disease phenotype in a mouse model of Huntington’s disease (Yang et al, 2017). Given that CRISPR/Cas9 can permanently eliminate the expression of targeted genes, use of this approach should be able to remove the mutant allele, thus preventing the production of the mutant protein and attenuating disease phenotype, especially in the condition with a dominant negative mutation like GABRG2(Q390X) .…”

Section: Gabamentioning

confidence: 99%

Defects at the crossroads of GABAergic signaling in generalized genetic epilepsies

Kang

2017

Epilepsy Research

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Seizure disorders are very common and affect 3% of the general population. The recurrent unprovoked seizures that are also called epilepsies are highly diverse as to both underlying genetic basis and clinic presentations. Recent genetic advances and sequencing technologies indicate that many epilepsies previously thought to be without known causes, or idiopathic generalized epilepsies (IGEs), are virtually genetic epilepsy as they are caused by genetic variations. IGEs are estimated to account for ~15-20% of all epilepsies. Initially IGEs were primarily considered channelopathies, because the first genetic defects identified in IGEs involved ion channel genes. However, new findings indicate that mutations in many non ion channel genes are also involved in addition to those in ion channel genes. Interestingly, mutations in many genes associated with epilepsy affect GABAergic signaling, a major biological pathway in epilepsy. Additionally, many antiepileptic drugs work via enhancing GABAergic signaling. Hence, the review will focus on the mutations that impair GABAergic signaling and selectively discuss the newly identified STXBP1, PRRT2, and DNM1 in addition to those long-established epilepsy ion channel genes that also impair GABAergic signaling like SCN1A and GABAA receptor subunit genes. GABAergic signaling includes the pre- and post- synaptic mechanisms. Some mutations, such as STXBP1, PRRT2, DNM1, and SCN1A, impair GABAergic signaling mainly via pre-synaptic mechanisms while those mutations in GABAA receptor subunit genes impair GABAergic signaling via post-synaptic mechanisms. Nevertheless, these findings suggest impaired GABAergic signaling is a converging pathway of defects for many ion channel or non ion channel mutations associated with genetic epilepsies.

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CRISPR/Cas9-mediated gene editing ameliorates neurotoxicity in mouse model of Huntington’s disease

Cited by 317 publications

References 21 publications

Huntington's disease: a clinical review

Huntington's disease: a clinical review

Mesenchymal stem cells alleviate AQP-4-dependent glymphatic dysfunction and improve brain distribution of antisense oligonucleotides in BACHD mice

Defects at the crossroads of GABAergic signaling in generalized genetic epilepsies

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