Gene Editing and Modulation: the Holy Grail for the Genetic Epilepsies?

Neurotherapeutics ◽

10.1007/s13311-021-01081-y ◽

2021 ◽

Author(s):

Jenna C. Carpenter ◽

Gabriele Lignani

Keyword(s):

Precision Medicine ◽

Neurological Disorder ◽

Gene Editing ◽

Therapeutic Strategy ◽

Therapeutic Potential ◽

Single Gene ◽

Drug Resistant ◽

Holy Grail ◽

Effective Therapeutic Strategy ◽

Genetic Epilepsies

AbstractEpilepsy is a complex neurological disorder for which there are a large number of monogenic subtypes. Monogenic epilepsies are often severe and disabling, featuring drug-resistant seizures and significant developmental comorbidities. These disorders are potentially amenable to a precision medicine approach, of which genome editing using CRISPR/Cas represents the holy grail. Here we consider mutations in some of the most ‘common’ rare epilepsy genes and discuss the different CRISPR/Cas approaches that could be taken to cure these disorders. We consider scenarios where CRISPR-mediated gene modulation could serve as an effective therapeutic strategy and discuss whether a single gene corrective approach could hold therapeutic potential in the context of homeostatic compensation in the developing, highly dynamic brain. Despite an incomplete understanding of the mechanisms of the genetic epilepsies and current limitations of gene editing tools, CRISPR-mediated approaches have game-changing potential in the treatment of genetic epilepsy over the next decade.

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Personalized Medicine Using Cutting Edge Technologies for Genetic Epilepsies

Current Neuropharmacology ◽

10.2174/1570159x18666200915151909 ◽

2020 ◽

Vol 18 ◽

Author(s):

Sheila Garcia-Rosa ◽

Bianca de Freitas Brenha ◽

Vinicius Felipe da Rocha ◽

Ernesto Goulart ◽

Bruno Henrique Silva Araujo

Keyword(s):

Therapeutic Potential ◽

Association Studies ◽

Individualized Medicine ◽

Disease Model ◽

Protein Structures ◽

Genetic Association Studies ◽

Drug Resistant ◽

Neurologic Disorder ◽

Core Elements ◽

Genetic Epilepsies

: Epilepsy is the most common chronic neurologic disorder in the world, affecting 1-2% of the population. Besides, 30% of epilepsy patients are drug-resistant. Genomic mutations seem to play a key role in its etiology and knowledge of strong effect mutations in protein structures might improve prediction and the development of efficacious drugs to treat epilepsy. Several genetic association studies have been undertaken to examine the effect of a range of candidate genes for resistance. Although, few studies have explored the effect of the mutations into protein structure and biophysics in the epilepsy field. Much work remains to be done, but the scene is set for exciting developments that will hold therapeutic potential for patients with drug-resistant. In summary, we provide a critical review of the perspectives for the development of individualized medicine for epilepsy based on genetic polymorphisms/mutations in light of core elements such as transcriptomics, structural biology, disease model, pharmacogenomics and pharmacokinetics in a manner to improve the success of trial designs of antiepileptic drugs.

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CRISPR to the Rescue: Advances in Gene Editing for the FMR1 Gene

Brain Sciences ◽

10.3390/brainsci9010017 ◽

2019 ◽

Vol 9 (1) ◽

pp. 17 ◽

Cited By ~ 6

Author(s):

Carolyn Yrigollen ◽

Beverly Davidson

Keyword(s):

Clinical Trials ◽

Fragile X Syndrome ◽

Gene Editing ◽

Therapeutic Strategy ◽

Therapeutic Potential ◽

Fragile X ◽

Genetic Disorders ◽

Treatment Strategies ◽

Gene Pathway ◽

Ataxia Syndrome

Gene-editing using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) is promising as a potential therapeutic strategy for many genetic disorders. CRISPR-based therapies are already being assessed in clinical trials, and evaluation of this technology in Fragile X syndrome has been performed by a number of groups. The findings from these studies and the advancement of CRISPR-based technologies are insightful as the field continues towards treatments and cures of Fragile X-Associated Disorders (FXADs). In this review, we summarize reports using CRISPR-editing strategies to target Fragile X syndrome (FXS) molecular dysregulation, and highlight how differences in FXS and Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) might alter treatment strategies for each syndrome. We discuss the various modifications and evolutions of the CRISPR toolkit that expand its therapeutic potential, and other considerations for moving these strategies from bench to bedside. The rapidly growing field of CRISPR therapeutics is providing a myriad of approaches to target a gene, pathway, or transcript for modification. As cures for FXADs have remained elusive, CRISPR opens new avenues to pursue.

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Nanopharmaceutical-based regenerative medicine: Promising therapeutic strategy for spinal cord injury

Journal of Materials Chemistry B ◽

10.1039/d0tb02740e ◽

2021 ◽

Author(s):

Chen Zhao ◽

Zheng Xing ◽

Chunchen Zhang ◽

Yubo Fan ◽

Haifeng Liu

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Regenerative Medicine ◽

Neurological Disorder ◽

Therapeutic Strategy ◽

Severe Injury ◽

Cord Injury

Spinal cord injury (SCI) is a neurological disorder that can lead to loss of perceptive and athletic function due to the severe injury of nerve. Nowadays, evidences detailing the precise...

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Anti-Biofilm Molecules Targeting Functional Amyloids

Antibiotics ◽

10.3390/antibiotics10070795 ◽

2021 ◽

Vol 10 (7) ◽

pp. 795

Author(s):

Leticia Matilla-Cuenca ◽

Alejandro Toledo-Arana ◽

Jaione Valle

Keyword(s):

Biofilm Formation ◽

Therapeutic Strategy ◽

Research Area ◽

Therapeutic Strategies ◽

Structural Components ◽

Significant Issue ◽

Wide Range ◽

Effective Therapeutic Strategy ◽

Functional Amyloids ◽

Biofilm Matrix

The choice of an effective therapeutic strategy in the treatment of biofilm-related infections is a significant issue. Amyloids, which have been historically related to human diseases, are now considered to be prevailing structural components of the biofilm matrix in a wide range of bacteria. This assumption creates the potential for an exciting research area, in which functional amyloids are considered to be attractive targets for drug development to dissemble biofilm structures. The present review describes the best-characterized bacterial functional amyloids and focuses on anti-biofilm agents that target intrinsic and facultative amyloids. This study provides a better understanding of the different modes of actions of the anti-amyloid molecules to inhibit biofilm formation. This information can be further exploited to improve the therapeutic strategies to combat biofilm-related infections.

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Therapeutic manipulation of IKBKAP mis-splicing with a small molecule to cure familial dysautonomia

Nature Communications ◽

10.1038/s41467-021-24705-5 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Masahiko Ajiro ◽

Tomonari Awaya ◽

Young Jin Kim ◽

Kei Iida ◽

Masatsugu Denawa ◽

...

Keyword(s):

Small Molecule ◽

Genetic Disease ◽

Therapeutic Strategy ◽

Therapeutic Potential ◽

Familial Dysautonomia ◽

Therapeutic Modality ◽

Aberrant Splicing ◽

Intronic Splicing Enhancer ◽

Exon 20 ◽

Splicing Enhancer

AbstractApproximately half of genetic disease-associated mutations cause aberrant splicing. However, a widely applicable therapeutic strategy to splicing diseases is yet to be developed. Here, we analyze the mechanism whereby IKBKAP-familial dysautonomia (FD) exon 20 inclusion is specifically promoted by a small molecule splice modulator, RECTAS, even though IKBKAP-FD exon 20 has a suboptimal 5′ splice site due to the IVS20 + 6 T > C mutation. Knockdown experiments reveal that exon 20 inclusion is suppressed in the absence of serine/arginine-rich splicing factor 6 (SRSF6) binding to an intronic splicing enhancer in intron 20. We show that RECTAS directly interacts with CDC-like kinases (CLKs) and enhances SRSF6 phosphorylation. Consistently, exon 20 splicing is bidirectionally manipulated by targeting cellular CLK activity with RECTAS versus CLK inhibitors. The therapeutic potential of RECTAS is validated in multiple FD disease models. Our study indicates that small synthetic molecules affecting phosphorylation state of SRSFs is available as a new therapeutic modality for mechanism-oriented precision medicine of splicing diseases.

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A toolmaker’s perspective on CRISPR-directed gene editing as a therapeutic strategy for leukemia and beyond

Expert Review of Hematology ◽

10.1080/17474086.2021.1935853 ◽

2021 ◽

Author(s):

Eric B. Kmiec ◽

Kevin Bloh

Keyword(s):

Gene Editing ◽

Therapeutic Strategy

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Metformin and Niclosamide Synergistically Suppress Wnt and YAP in APC-Mutated Colorectal Cancer

Cancers ◽

10.3390/cancers13143437 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3437

Author(s):

Hee Eun Kang ◽

Yoojeong Seo ◽

Jun Seop Yun ◽

Sang Hyun Song ◽

Dawool Han ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Progression ◽

Therapeutic Strategy ◽

Target Gene ◽

Advanced Colorectal Cancer ◽

Therapeutic Potential ◽

Cancer Stemness ◽

Reciprocal Regulation ◽

Canonical Wnt

The Wnt and Hippo pathways are tightly coordinated and understanding their reciprocal regulation may provide a novel therapeutic strategy for cancer. Anti-helminthic niclosamide is an effective inhibitor of Wnt and is now in a phase II trial for advanced colorectal cancer (CRC) patients. We found that Axin2, an authentic target gene of canonical Wnt, acts as aYAP phosphorylation activator in APC-mutated CRC. While niclosamide effectively suppresses Wnt, it also inhibits Hippo, limiting its therapeutic potential for CRC. To overcome this limitation, we utilized metformin, a clinically available AMPK activator. This combinatory approach not only suppresses canonical Wnt activity, but also inhibits YAP activity in CRC cancer cells and in patient-derived cancer organoid through the suppression of cancer stemness. Further, combinatory oral administration suppressed in vivo tumorigenesis and the cancer progression of APC-MIN mice models. Our observations provide not only a reciprocal link between Wnt and Hippo, but also clinically available novel therapeutics that are able to target Wnt and YAP in APC-mutated CRC.

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Precision Medicine in Neurodegenerative Diseases: Some Promising Tips Coming from the microRNAs’ World

Cells ◽

10.3390/cells9010075 ◽

2019 ◽

Vol 9 (1) ◽

pp. 75 ◽

Cited By ~ 3

Author(s):

Nicoletta Nuzziello ◽

Loredana Ciaccia ◽

Maria Liguori

Keyword(s):

Neurodegenerative Diseases ◽

Precision Medicine ◽

Target Genes ◽

Drug Disposition ◽

Therapeutic Potential ◽

Response To Treatment ◽

Therapeutic Effects ◽

Exciting Potential ◽

The Central Nervous System ◽

Effective Use

Novel insights in the development of a precision medicine approach for treating the neurodegenerative diseases (NDDs) are provided by emerging advances in the field of pharmacoepigenomics. In this context, microRNAs (miRNAs) have been extensively studied because of their implication in several disorders related to the central nervous system, as well as for their potential role as biomarkers of diagnosis, prognosis, and response to treatment. Recent studies in the field of neurodegeneration reported evidence that drug response and efficacy can be modulated by miRNA-mediated mechanisms. In fact, miRNAs seem to regulate the expression of pharmacology target genes, while approved (conventional and non-conventional) therapies can restore altered miRNAs observed in NDDs. The knowledge of miRNA pharmacoepigenomics may offers new clues to develop more effective treatments by providing novel insights into interindividual variability in drug disposition and response. Recently, the therapeutic potential of miRNAs is gaining increasing attention, and miRNA-based drugs (for cancer) have been under observation in clinical trials. However, the effective use of miRNAs as therapeutic target still needs to be investigated. Here, we report a brief review of representative studies in which miRNAs related to therapeutic effects have been investigated in NDDs, providing exciting potential prospects of miRNAs in pharmacoepigenomics and translational medicine.

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