New CRISPR/Cas9 technology can disposable corrected DMD patients thousands of mutations

Source: the new CRISPR/Cas9 technology can disposable corrected DMD patients thousands of mutations

From Texas University UT southwest Medical Center scientists recently published research report, they use athe CRISPR/Cas9 gene editing technologycorrect the cause of theDuchenne muscular dystrophy（DMD）3000 kinds of genetic mutationsmost of the mutantit. In the proof-of-concept study, Eric Olson Dr. and his colleagues use thesingle cut myoediting technology, succeed in derived from DMD patients and carry a number of different DMD mutations in the cells to recover.normal dystrophin protein dystrophin）production. In 3D engineered cardiac muscle of DMD mutations myoediting successful recovery.myocardial cells in dystrophin protein expression and contractile forceit.

According to reports, this new method required in the DMD gene specific loci on a single cut, and can be eliminated for each DMD mutation alone develop agene editing toolsof necessity. UT Southwestern Medical Center in regenerative science and medicine, Hamon Center Director Olson, said Dr. this is very important progress, and we hope this technology can eventually reduce thecarries a wide range of types of mutations of DMDthe patient’s suffering or even save their life.

This study has been recently published in the Science Advancesonscience progressand is entitled“Correction of Diverse Muscular Dystrophy Mutations in Human Engineered Heart Muscle by Single-Site Genome Editing using single point genome editing in the artificial process in the muscle to correct a variety of different DMD mutations）”。

DMD inmenthe incidence of1/5000, the disease is a byX-linked mutations in the dystrophin genecaused by the genetic diseaseit. The DMD gene has a260 million base pairs, is the human genome, the largest known gene, its size and complex structure lead to a very high spontaneous mutation rate. As of now, it has been recorded in the case of DMD gene mutations in as many as 3,000 species, including thelarge fragment deletion or duplication, small fragment deletions, and point mutationsit.

Olson, Dr. the research team and other research teams have previously used CRISPR/Cas9-mediated genome editing techniques to correct a mouse model ofthe DMD gene point mutationsit. However, as the researchers noted that the majority of DMD patients carry mutations is one or more exon deletion mutations, and only5%-9%of DMD patients carry a point mutation. Given that in humans identified thousands of mutations, one obvious problem is that such a large number of mutations exactly what to do to get by CRISPR/Cas9-mediated genome editing technology to correct.

In fact, the majority of DMD mutations to cluster in the gene“hotspots hotspot”in the region of exons 45 to 50, and exon 2 to 29）it. This means that the skip is located in“hotspots”within or near the 12 target exons, called the top 12 exons in 1 or 2 and thus eliminate the abnormal splice sites, can be effective in theabout 60%of DMD patients to produce a functional dystrophin protein. In this study, the team created the“myoediting”is by means of exon skipping to correct the DMD genetic mutation.

In the study, the research team screened can be guided Cas9 enzyme to skip the DMD gene before the 12 exons and is able to restore a functional dystrophin protein generated by the guide RNA. Its purpose is to develop agroup of mutationsthe role of CRISPR/Cas9 tools, thereby skipping of a single exon can restore most patients todystrophin expressionit.

In the study, the team optimized theguide RNA, usingmyoediting technologyfrom DMD patients and presented a wide variety ofDMD mutations.Includes a large segment deletions, point mutations, sequence duplication mutation, etc.cardiomyocytesinduced pluripotent stem cells iPSC）, restore the dystrophin protein production.

In addition, the use of3DEHMfor the testing also found that the use of a single guide RNA to myoediting DMD gene mutation also successfully restored dystrophin expression and muscle contraction force. It is reassuring that the study found thatno needcorrect the myocardial model in each myocardial cell within the dystrophin protein production, whereasjust to correct a group of myocardial cells in 30% to 50% of theis enough to save mutation of the EHM table type, make it close to normal control level.

The study’s co-author, UT Southwestern Medical Center Molecular Biology Professor Rhonda Bassel Duby said Dr, this is a very significant progress. Currently, scientists have proposed many different methods of treatment, but myoediting to extend the lives of patients and improve quality of life provides a real hope. We not only found a practical approach to the treatment of many mutations, but also developed a less destructive method to skip the defective DNA rather than remove them.< strong>the genome is highly structured, you do not want to delete might be very important DNA fragments.

According to the study, the samesingle cut the CRISPR/Cas9 methodcan also be effectively developed for use bysingle-gene mutationslead to other treatment of disease. However, with the proviso that the target exon is removed, the target gene must be able to function. Olson, Dr. noted that dystrophin is like a shock absorber, remove a few rings of the spring are also possible. But other proteins may not be so easy.

In 2017, 2 months, Olson Dr has founded startupsExonics Therapeutics, the company from the UT Southwestern Medical Center authorized to obtain the CRISPR/Cas9 technology development for the treatment of DMD drugs. Before this new company from CureDuchenne Ventures earned 500 million USD of seed financing.< strong>（Sina medicine compiled/newborn）

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Published at Wed, 11 Feb 2018 21:57:30 +0000