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Applications of CRISPR-Cas9 in the Treatment of Alzheimer's Disease    

Overview of Alzheimer's Disease

Alzheimer's disease (AD) is one of the main causes of death in the elderly population. Genetic studies on AD patients have revealed the relationship between the mutation in genes and the onset of symptoms. Early-onset familial AD is caused by the mutation in the gene encoding presenilins (PSEN1 and PSEN2) and amyloid precursor protein (APP). Mutation in the APOE gene that transcribes apolipoprotein E protein was considered to be a risk factor for late-onset AD. After the onset of symptoms, such as dementia, mood swings, cognitive impairment, and loss of motivation, the disease rapidly progresses and leads to death. Acclimation of the neurofibrillary tangles and amyloid plaques in the neurons, which are formed because of the clipping of Amyloid Precursor Protein (APP) by the enzymes Beta-Secretase (BACE1) and the Gamma-Secretase, are the characteristics of AD. Variants in the APP, such as Swedish mutation have been found to increase Beta–Secretase, thereby potentiating the APP cleavage and amyloid plaque formation.

CRISPR/Cas9 System

The emergence of the beta-amyloid hypothesis provided the impetus for the development and testing of the first known disease-modifying therapeutics, which collectively had an action of either preventing beta-amyloid from forming or resulted in enhanced clearance out of the brain. Unfortunately, since the last Alzheimer's drug-which only temporarily treats the symptoms of the disease–was approved more than a decade ago, these clinical trials have failed resoundingly, with more than 400 failed clinical trials. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-associated protein (Cas9) constitutes a recently developed powerful genome editing tool, which has the potential to treat diseases for which treatments are still lacking or ineffective. CRISPR/Cas9 can target almost any gene in a sequence-dependent manner, and its targeting efficiency is higher than other gene targeting methods. Therefore, this system could be applied to any number of autosomal-dominant mutations causing early-onset AD, or for those genetic risk factors that enhance the dementia risk associated with late-onset AD, especially the APOE4 allele.

Potential Therapeutic Applications of CRISPR/Cas9 in AD

Many studies have used the CRISPR-Cas9 system in familial AD patient induced pluripotent stem cell (iPSC) lines to produce isogenic controls without the causal mutation. Ortiz Virumbrales et al. used CRISPR-Cas9 in iPSC neurons derived from a patient carrying the PSEN2 N141I mutation to correct the autosomal dominant mutation, which resulted in the normalization of the Aβ42/40 ratio. The generation of gene-corrected isogenic control iPSC lines from patients has also been performed in patient lines bearing the PSEN1 mutations A79V and L150P and constitutes a useful in vitro disease model to investigate the mechanisms underlying familial AD and the results of Aβ pathology. Using patient derived fibroblasts with the Swedish mutation, Gyorgy et al. recently disrupted the cleavage site and observed a 60% reduction in Aβ production. Park et al. targeted BACE1, using self-assembling nanocomplexes of the amphiphilic R7L10 peptide to package the Cas9 and gRNA constructs. Injection of the nanocomplexes into the hippocampus of the 5xFAD transgenic AD mouse model showed about 70% reduction in BACE1 expression. This was accompanied by an up to 15% decrease in hippocampal plaque burden and correlated with improvements in behavioral tests. In conclusion, these strategies demonstrate the capability of CRISPR-Cas9 to modulate gene expression in patient derived iPSC lines and reduce pathology in transgenic mouse models of familial AD, by successfully regulating the amyloidogenic pathway.

Interrogation of AD-associated gene mutations using iPSC technology and CRISPR-Cas9 gene editing to generate isogenic control cell lines. Figure 1. Interrogation of AD-associated gene mutations using iPSC technology and CRISPR-Cas9 gene editing to generate isogenic control cell lines. (Schrauben M, et al., 2020)

Regarding an important role of chronic neuroinflammation in the AD pathogenesis, a proinflammatory molecule called Glia maturation factor (GMF) is significantly up-regulated in different parts of AD brains. Besides, reactive glial cells surrounding the amyloid plaques (APs) in the AD brain are the central location of GMF expression. Inflammatory factors such as GMF and proinflammatory cytokines are mainly secreted by microglia. The activation of the microglial cells initiates a cascade of events that ultimately result in neurodegeneration and AD pathophysiology. The researchers conducted a study to confirm the hypothesis that CRISPR/Cas9-mediated GMF gene editing directs to the elimination of microglial activation, in which the results were significant. It showed that GMF gene editing causes inhibition of the inflammatory signaling pathway with suppression of MAPK which was revealed to be upregulated in AD patients. In general, GMF gene editing by CRISPR/Cas9 is considered as a new therapeutic strategy for AD.

Our CRISPR/Cas9 System Services

CRISPR/Cas9 PlatformCB is committed to providing the most professional and comprehensive genetic editing technology solutions for our clients. To support your projects, we offer a comprehensive custom CRISPR/Cas9 gene editing service from strategy design to final AD model generation.

➢ Human Cell Models Generation of AD by CRISPR/Cas9 System
➢ Animal Models Generation of AD by CRISPR/Cas9 System

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References

  1. Kolli N, et al. Application of the gene editing tool, CRISPR-Cas9, for treating neurodegenerative diseases. Neurochemistry international, 2018, 112: 187-196.
  2. Schrauben M, et al. Applying gene-editing technology to elucidate the functional consequence of genetic and epigenetic variation in Alzheimer's disease. Brain Pathology, 2020, 30(5): 992-1004.
  3. Karimian A, et al. CRISPR/Cas9 novel therapeutic road for the treatment of neurodegenerative diseases. Life Sciences, 2020: 118165.
  4. Raikwar S P, et al. Targeted gene editing of glia maturation factor in microglia: a novel Alzheimer's disease therapeutic target. Molecular neurobiology, 2019, 56(1): 378-393.
  5. Van Giau V, et al. Genome-editing applications of CRISPR–Cas9 to promote in vitro studies of Alzheimer's disease. Clinical interventions in aging, 2018, 13: 221.
  6. Rohn T T, et al. The potential of CRISPR/Cas9 gene editing as a treatment strategy for Alzheimer's disease. Journal of Alzheimer's disease & Parkinsonism, 2018, 8(3).
  7. Hanafy A S, et al. CRISPR/Cas9 Delivery Potentials in Alzheimer's Disease Management: A Mini Review. Pharmaceutics, 2020, 12(9): 801.
For research use only. Not intended for any clinical use.
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