CRISPR-Cas9 Mediated Gene-Silencing of the Mutant Huntingtin Gene in an In Vitro Model of Huntington’s Disease

Identification of molecules able to promote neuroprotective mechanisms can represent a promising therapeutic approach to neurodegenerative disorders including Huntington’s disease. Curcumin is an antioxidant and neuroprotective agent, even though its efficacy is limited by its poor absorption, rapid metabolism, systemic elimination, and limited blood–brain barrier (BBB) permeability. Herein, we report on novel biodegradable curcumin-containing nanoparticles to favor the compound delivery and potentially enhance its brain bioavailability. The prepared hyaluronan-based materials able to self-assemble in stable spherical nanoparticles, consist of natural fatty acids chemically conjugated to the natural polysaccharide. The aim of this study is to provide a possible effective delivery system for curcumin with the expectation that, after having released the drug at the specific site, the biopolymer can degrade to nontoxic fragments before renal excretion, since all the starting materials are provided by natural resource. Our findings demonstrate that curcumin-encapsulated nanoparticles enter the cells and reduce their susceptibility to apoptosis in an in vitro model of Huntington’s disease.

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Inhibition of Aggregation of Mutant Huntingtin by Nucleic Acid Aptamers In Vitro and in a Yeast Model of Huntington’s Disease

Gene Therapy in Neurological Disorders ◽

10.1016/b978-0-12-809813-4.00010-7 ◽

2018 ◽

pp. 207-228

Author(s):

Rajeev K. Chaudhary ◽

Kinjal A. Patel ◽

Ipsita Roy

Keyword(s):

Nucleic Acid ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Mutant Huntingtin ◽

Nucleic Acid Aptamers ◽

Yeast Model

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Silencing of the Mutant Huntingtin Gene through CRISPR-Cas9 Improves the Mitochondrial Biomarkers in an In Vitro Model of Huntington’s Disease

Cell Transplantation ◽

10.1177/0963689719840662 ◽

2019 ◽

Vol 28 (4) ◽

pp. 460-463 ◽

Cited By ~ 1

Author(s):

Gary L. Dunbar ◽

Sindhuja Koneru ◽

Nivya Kolli ◽

Michael Sandstrom ◽

Panchanan Maiti ◽

...

Keyword(s):

Gene Editing ◽

In Vitro Model ◽

Mutant Huntingtin ◽

Therapeutic Tool ◽

Neural Therapy ◽

Viral Genes ◽

History Of ◽

Vitro Model ◽

American Society

During the 25-year history of the American Society for Neural Therapy and Repair (ASNTR) there have been several breakthroughs in the area of neurotherapeutics, which was the case during the 2014–2105 year when one of us (GLD) had the privilege of serving as its president. During that year, the use of a newly developed gene-editing tool, the CRISPR-Cas9 system, started to skyrocket. Although scientists unraveled the use of “clustered regularly interspaced short palindromic repeats” (CRISPR) and its associated genes from the Cas family as an evolved mechanism of some bacterial and archaeal genomes to protect themselves from being hijacked by invasive viral genes, its use as a therapeutic tool was not fully appreciated until further research revealed how this system operated and how it might be developed technologically to manipulate genes of any species. By 2015, this technology had exploded to the point that close to 2,000 papers that used this technology were published during that year alone.

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Clioquinol down-regulates mutant huntingtin expression in vitro and mitigates pathology in a Huntington's disease mouse model

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0502177102 ◽

2005 ◽

Vol 102 (33) ◽

pp. 11840-11845 ◽

Cited By ~ 136

Author(s):

T. Nguyen ◽

A. Hamby ◽

S. M. Massa

Keyword(s):

Mouse Model ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Mutant Huntingtin

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The Ubiquitin-Proteasome System in Huntington’s Disease: Are Proteasomes Impaired, Initiators of Disease, or Coming to the Rescue?

Biochemistry Research International ◽

10.1155/2012/837015 ◽

2012 ◽

Vol 2012 ◽

pp. 1-12 ◽

Cited By ~ 35

Author(s):

Sabine Schipper-Krom ◽

Katrin Juenemann ◽

Eric A. J. Reits

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Protein A ◽

Ubiquitin Proteasome System ◽

Mutant Huntingtin ◽

Polyglutamine Expansion ◽

Ubiquitin Proteasome ◽

Intracellular Aggregates ◽

Polyglutamine Aggregation

Huntington’s disease is a progressive neurodegenerative disease, caused by a polyglutamine expansion in the huntingtin protein. A prominent hallmark of the disease is the presence of intracellular aggregates initiated by N-terminal huntingtin fragments containing the polyglutamine repeat, which recruit components of the ubiquitin-proteasome system. While it is commonly thought that proteasomes are irreversibly sequestered into these aggregates leading to impairment of the ubiquitin-proteasome system, the data on proteasomal impairment in Huntington’s disease is contradictory. In addition, it has been suggested that proteasomes are unable to actually cleave polyglutamine sequencesin vitro, thereby releasing aggregation-prone polyglutamine peptides in cells. Here, we discuss how the proteasome is involved in the various stages of polyglutamine aggregation in Huntington’s disease, and how alterations in activity may improve clearance of mutant huntingtin fragments.

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