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Aging and disease
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The Impact of CRISPR-Cas9 on Age-related Disorders: From Pathology to Therapy
Allen Caobi1, Rajib Kumar Dutta1, Luis D. Garbinski3, Maria Esteban-Lopez2, Yasemin Ceyhan2, Mickensone Andre1, Marko Manevski1, Chet Raj Ojha1, Jessica Lapierre1, Sneham Tiwari1, Tiyash Parira1, Nazira El-Hage1
1Departments of Immunology and Nano-medicine,
2Human and Molecular Genetics and
3Cell Biology and Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, USA.
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Abstract  

With advances in medical technology, the number of people over the age of 60 is on the rise, and thus, increasing the prevalence of age-related pathologies within the aging population. Neurodegenerative disorders, cancers, metabolic and inflammatory diseases are some of the most prevalent age-related pathologies affecting the growing population. It is imperative that a new treatment to combat these pathologies be developed. Although, still in its infancy, the CRISPR-Cas9 system has become a potent gene-editing tool capable of correcting gene-mediated age-related pathology, and therefore ameliorating or eliminating disease symptoms. Deleting target genes using the CRISPR-Cas9 system or correcting for gene mutations may ameliorate many different neurodegenerative disorders detected in the aging population. Cancer cells targeted by the CRISPR-Cas9 system may result in an increased sensitivity to chemotherapeutics, lower proliferation, and higher cancer cell death. Finally, reducing gene targeting inflammatory molecules production through microRNA knockout holds promise as a therapeutic strategy for both arthritis and inflammation. Here we present a review based on how the expanding world of genome editing can be applied to disorders and diseases affecting the aging population.

Keywords gene-editing      aging      CRISPR-Cas9      neurodegeneration      cancer      alternative medicine     
About author:

These authors contributed equally to this work.

Just Accepted Date: 11 October 2019  
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Allen Caobi
Rajib Kumar Dutta
Luis D. Garbinski
Maria Esteban-Lopez
Yasemin Ceyhan
Mickensone Andre
Marko Manevski
Chet Raj Ojha
Jessica Lapierre
Sneham Tiwari
Tiyash Parira
Nazira El-Hage
Cite this article:   
Allen Caobi,Rajib Kumar Dutta,Luis D. Garbinski, et al. The Impact of CRISPR-Cas9 on Age-related Disorders: From Pathology to Therapy[J]. Aging and disease, 10.14336/AD.2019.0927
URL:  
http://www.aginganddisease.org/EN/10.14336/AD.2019.0927     OR     http://www.aginganddisease.org/EN/Y/V/I/0
Figure 1.  Prevalence of age-associated disorders that can be targeted by the CRISPR-Cas9 technology. Schematic diagram of the health burden associated with increased life expectancy in men (depicted in blue color) and women (depicted in pink color). Neurodegenerative disorders, cancer, metabolic and inflammatory diseases are among the most prevalent age-related pathologies affecting the growing population.
DisordersTarget SitesModelAdvantagesDisadvantagesRefs
Amyotrophic Lateral Sclerosis (ALS)SOD1 and FUSHuman ALS patient fibroblastCorrects the mutation A272C in SOD1 and G1566A in FUS.Not clear if treatment after disease onset would be effective.
Reduces the expression of both wild type and mutant gene.
(51)
tardbp and fusZebrafishCorrection of missense mutations in these ALS-associated genes.N/A*(55)

Alzheimer’s Disease (AD)
Mutation in Amyloid Precursor Protein (APP)HumanDisrupts expression of mutant APP.Shortening the gRNA could lead to decreased on-target efficacy(66; 75)
PSEN2Basal forebrain cholinergic neuronsCorrection of the N141I mutation resulted in normalization of observed Aβ42/40 increase.N/A*(73)
PSEN2HumanAbolishes the electrophysiological deficit and restores the number of spikes and spike height.N/A*(73)
PSEN1Human(c.236 T > C) mutation correction.N/A*(71)
PSEN1Human(c.449C > T) mutation correction of the PSEN1 gene.N/A*(72)
APOE4HumanConverts APOE4 to APOE2 or E3.
Effective in neutralizing the risk of AD.
N/A*(68)

Parkinson’s Disease (PD)
LRRK2HumanCorrects the p.G2019S mutation in LRRK2 and neurite complexity.
Retained pluripotency of hiPSCs after gene editing.
N/A*(102)
SNCAHuman cell lineCorrects mutation in SNCA gene.N/A*(103)
Colorectal Cancer
(CRC)
PAR3LHuman CaCO-2 CellsKO results in reduced proliferation and induction of apoptosis of CRC cell line.Study was limited to CRC cell lines, no primary cells used.(38)
TP53Human colon adenocarcinoma-derived cell linesCorrection of mutations of TP53 at exon 3 and exon 10 may alter the malignant potential of these cells.Not tested on all of the genomic mutations and clinical varieties of TP53.(131)
APCHuman and mouse organoidsColonoscopy-guided mucosal injection used to deliver CRISPR-engineered organoids.
Facilitates studying adenoma-carcinoma-metastasis progression.
Colonoscopy and specific surgical equipment are required.(139)
KRASHuman cell linessgRNA library targeting protein-coding genes in KRAS-mutant CRC cell lines used to identify genes associated with reduced tumor growth.N/A*(36)

Prostate Cancer
PD-1Phase I clinical trialPD-1 knockdown of T cells in castration-resistant prostate cancer.Confirmation of successful knockdown and a significant change in disease phenotype cannot yet be made, as the clinical trial is ongoing.(152)
GPRC6A Human cell lineReduces primary tumor growth.N/A*(148)
Androgen receptor (AR) geneHuman Cell lineRestrains growth of androgen-dependent prostate cancer and potential therapeutic strategy for prostate cancer treatment.Limited to androgen-dependent prostate cancer not androgen-independent prostate cancer.(146)
Transcription factor NANOG andpseudogene NANOGP8Human cell lineAttenuates malignant potential and migration capability.Knockout of both NANOG1 and NANOGP8 genes is lethal.(150)

Breast Cancer
HER2Human cell lineInhibits cell growth and tumorgenicity.Effects downstream MAPK/ERK and PI3K/AKT signaling cascades, in non-cancer cells.(163)
PtenMouse modelPten silencing by lentiviral delivery results in development of invasive lobular breast cancer.Lentiviral delivery causes immune response.(161)
CDK8/19Human cell lineSuppress estrogen-induced gene expression in breast cancer.N/A*(169)
Ubr5MiceImpairs tumor growth and metastasis.N/A*(170)
MIEN1Human epithelial breast cancerDeletions of MIEN1 gene lead to the abrogation of breast cancer.N/A*(171)
Ovarian CancerDNMT1Human ovarian cancer cell line (SKOV-3) and miceInhibition of tumor growthN/A*(175; 176)
MTH1A subcutaneous xenograft tumor model of SKOV3 cells in BALB/c nude miceApoptosis and genetic damage of cancerous cells resulting in tumor growth inhibition.N/A*(177)
miR-21Human ovarian cancer cell lines (SKOV-3 & OVCAR3)Inhibition of the epithelial-to-mesenchymal transition (EMT) in ovarian cancer cells.N/A*(178)
PARP-1SKOV-3 cell line and a SKOV-3 xenograft BALB/C mice modelIncreased cancer cell deathN/A*(179)
Rheumatoid arthritisFOXP3-associated genesHuman Regulatory T-cell (Treg)Augmentation of the suppressive ability of Tregs via increased Treg stability.
Insertion of chimeric antigen receptor (CAR) gene increased potency in cancer therapy.
N/A*(181)
Lung infectionMUC18
Human primary airway epithelial cells (AECs)Reduced IL-8 (proinflammatory chemokine) responses.Mixed population of edited cells and phenotypic changes unrelated to the gene knockout.(12)
Table 1  Therapeutic applications of CRISPR-Cas9 system in age-related disorders.
Table 1  includes a list of diseases related to the aging population that the CRISPR technology has been used for. Included in the list are the target sites, models, advantages and obstacles of using CRISPR-Cas9 technology.
Figure 2.  CRISPR-Cas9 system and age-related disorder target genes. Schematic representation of the CRISPR-Cas9 mediated genome editing and potential target genes associated with ALS, AD, PD, HD, cancers and inflammatory disorders. The functional gene may be inserted (green box), the mutated gene may be replaced with a wild-type gene (yellow box) or be removed altogether (red box).
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