CRISPR deletion of the C9ORF72 promoter in ALS/FTD patient motor neurons abolishes production of dipeptide repeat proteins and rescues neurodegeneration

Krishnan, Gopinath; Zhang, Yu; Gu, Yuanzheng; Kankel, Mark W.; Gao, Fen‐Biao; Almeida, Sandra

doi:10.1007/s00401-020-02154-6

Cited by 25 publications

(22 citation statements)

References 14 publications

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“…To achieve results in the ND field, the potentially important targets for CRISPR/Cas9‐based research should be focused on aberrant protein aggregation and redox mechanisms and pathways. These relate to proteins and enzymes from the redox metabolism, mitochondrial bioenergetics and transport, and the regulated cell death programs, that have all been identified as strongly associated with the pathogenesis of neurodegeneration 136–138 …”

Section: Novel Approaches For Neurodegenerative Disease Treatmentmentioning

confidence: 99%

Mitochondria and lipid peroxidation in the mechanism of neurodegeneration: Finding ways for prevention

Angelova

Esteras

Abramov

2020

Medicinal Research Reviews

188

119

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The world's population aging progression renders age‐related neurodegenerative diseases to be one of the biggest unsolved problems of modern society. Despite the progress in studying the development of pathology, finding ways for modifying neurodegenerative disorders remains a high priority. One common feature of neurodegenerative diseases is mitochondrial dysfunction and overproduction of reactive oxygen species, resulting in oxidative stress. Although lipid peroxidation is one of the markers for oxidative stress, it also plays an important role in cell physiology, including activation of phospholipases and stimulation of signaling cascades. Excessive lipid peroxidation is a hallmark for most neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and many other neurological conditions. The products of lipid peroxidation have been shown to be the trigger for necrotic, apoptotic, and more specifically for oxidative stress‐related, that is, ferroptosis and neuronal cell death. Here we discuss the involvement of lipid peroxidation in the mechanism of neuronal loss and some novel therapeutic directions to oppose it.

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Section: Novel Approaches For Neurodegenerative Disease Treatmentmentioning

confidence: 99%

Mitochondria and lipid peroxidation in the mechanism of neurodegeneration: Finding ways for prevention

Angelova

Esteras

Abramov

2020

Medicinal Research Reviews

188

119

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“…ASO [ 21 , 48 , 49 , 51 ] and CRISPR manipulations [ 52 ] have great therapeutic potential for C9-ALS/FTD. However, such therapies may also affect C9orf72 transcripts that originate from the normal allele.…”

Section: Discussionmentioning

confidence: 99%

Characterization of C9orf72 haplotypes to evaluate the effects of normal and pathological variations on its expression and splicing

et al. 2021

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Expansion of the hexanucleotide repeat (HR) in the first intron of the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in Caucasians. All C9orf72-ALS/FTD patients share a common risk (R) haplotype. To study C9orf72 expression and splicing from the mutant R allele compared to the complementary normal allele in ALS/FTD patients, we initially created a detailed molecular map of the single nucleotide polymorphism (SNP) signature and the HR length of the various C9orf72 haplotypes in Caucasians. We leveraged this map to determine the allelic origin of transcripts per patient, and decipher the effects of pathological and normal HR lengths on C9orf72 expression and splicing. In C9orf72 ALS patients’ cells, the HR expanded allele, compared to non-R allele, was associated with decreased levels of a downstream initiated transcript variant and increased levels of transcripts initiated upstream of the HR. HR expanded R alleles correlated with high levels of unspliced intron 1 and activation of cryptic donor splice sites along intron 1. Retention of intron 1 was associated with sequential intron 2 retention. The SNP signature of C9orf72 haplotypes described here enables allele-specific analysis of transcriptional products and may pave the way to allele-specific therapeutic strategies.

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“…CRISPR-Cas9 excision of the repeat sequence reduces some of the pathological hallmarks of the diseases, including repeat RNA foci and DPR proteins. A recent study has also demonstrated that a similar reduction in DPR proteins and a rescue of neurodegeneration can be achieved by using CRISPR to selectively delete the C9orf72 promoter region 55 . However, before CRISPR-Cas9 technology may be of therapeutic use in C9orf72 -linked ALS, it will be important to address the problem of potentially introducing insertion/deletion events into the wild-type allele, which may have functional consequences to the C9orf72 gene 56 .…”

Section: Gene Therapiesmentioning

confidence: 93%

Recent advances in understanding amyotrophic lateral sclerosis and emerging therapies

Gittings¹,

Sattler²

2020

Fac Rev

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is characterized by degeneration of both upper and lower motor neurons and subsequent progressive loss of muscle function. Within the last decade, significant progress has been made in the understanding of the etiology and pathobiology of the disease; however, treatment options remain limited and only two drugs, which exert a modest effect on survival, are approved for ALS treatment in the US. Therefore, the search for effective ALS therapies continues, and over 60 clinical trials are in progress for patients with ALS and other therapeutics are at the pre-clinical stage of development. Recent advances in understanding the genetics, pathology, and molecular mechanisms of ALS have led to the identification of novel targets and strategies that are being used in emerging ALS therapeutic interventions. Here, we review the current status and mechanisms of action of a selection of emerging ALS therapies in pre-clinical or early clinical development, including gene therapy, immunotherapy, and strategies that target neuroinflammation, phase separation, and protein clearance.

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CRISPR deletion of the C9ORF72 promoter in ALS/FTD patient motor neurons abolishes production of dipeptide repeat proteins and rescues neurodegeneration

Cited by 25 publications

References 14 publications

Mitochondria and lipid peroxidation in the mechanism of neurodegeneration: Finding ways for prevention

Mitochondria and lipid peroxidation in the mechanism of neurodegeneration: Finding ways for prevention

Characterization of C9orf72 haplotypes to evaluate the effects of normal and pathological variations on its expression and splicing

Recent advances in understanding amyotrophic lateral sclerosis and emerging therapies

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