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Developmental Biology - Gene Editing

A New Technology for Gene Editing

Salk scientists develop a new gene-editing tool that could help treat many disorders caused by gene mutations...

The ability to edit genes in living organisms offers the opportunity to treat a plethora of inherited diseases. However, many types of gene-editing tools are unable to target critical areas of DNA, and creating such a technology has been difficult as living tissue contains diverse types of cells.

Now, Salk Institute researchers have developed a new tool - dubbed SATI - to edit the mouse genome and enable them to target a broad range of mutations and cell types. The new genome-editing technology, published in Cell Research on August 23, 2019, can be used in a broad range of gene mutations such as Huntington's disease and the rare aging syndrome, Progeria.

"This study has shown that SATI is a powerful tool for genome editing," says Juan Carlos Izpisua Belmonte, a professor in Salk's Gene Expression Laboratory and senior author of the paper. "It could prove instrumental in developing effective strategies to target-gene replacement in many types of mutations, opening the door for genome-editing tools to possibly cure a broad range of genetic diseases."
Techniques that modify DNA, notably CRISPR-Cas9, are generally more effective on frequently dividing cells as seen in skin and gut. CRISPR-Cas9 works using a cells' normal DNA repair mechanism.

The Izpisua Belmonte lab previously showed that CRISPR/Cas9-based gene-editing technology — homology-independent targeted integration or HITI for short — can target both dividing and non-dividing cells. Protein-coding regions function as recipes for making proteins. Areas called non-coding regions act as chefs deciding how much food to make. Non-coding regions are ~98% of DNA and regulate many cell functions. This includes turning genes off and on, and could be a valuable target for future gene therapies.

"We sought to create a versatile tool to target these non-coding regions of DNA, which would not affect the function of the gene yet enable the targeting of a broad range of mutations and cell types," explained Mako Yamamoto, co-first author on the paper and a postdoctoral fellow in the Izpisua Belmonte lab. "As a proof-of-concept, we focused on a mouse model of premature aging caused by a mutation difficult to repair using existing genome-editing tools."
Salk researchrs' new gene knock-in method, is called intercellular linearized Single homology Arm donor mediated intron-Targeting Integration or SATI for short. It advances the previous HITI method by enabling it to target more of the genome.

SATI works by inserting a normal copy of the problematic gene into the non-coding region of DNA in front of the mutation site. This new gene becomes integrated into the genome alongside the old gene via one of several DNA repair pathways, relieving an organism of detrimental effects by the original, mutated gene, without risking damage from fully replacing it.
Scientists tested their SATI technology in living mice suffering with progeria, caused by a mutation in the LMNA gene. Both humans and mice with Progeria show signs of premature aging, cardiac dysfunction and dramatically shortened life span due to the accumulation of a protein called progerin.

By using SATI, a normal copy of LMNA gene was inserted into the Progeria mice. Researchers then observed diminished features of aging in several tissues including skin and spleen, and an extension of these mice life spans (45% increase as compared to untreated Progeria mice). A similar life span extension in humans, would be more than a decade. Thus, the SATI system represents the first in vivo gene correction technology that can target non-coding regions of DNA in multiple tissue types.

Next, the team wants to improve the efficiency of SATI by increasing the number of cells that incorporate new DNA.

"Specifically, we will investigate details of cell systems involved in DNA repair to refine SATI technology even further for better DNA correction," says Reyna Hernandez-Benitez, co-first author on the paper and postdoctoral fellow in the Izpisua Belmonte lab.

In vivo genome editing represents a powerful strategy for both understanding basic biology and treating inherited diseases. However, it remains a challenge to develop universal and efficient in vivo genome-editing tools for tissues that comprise diverse cell types in either a dividing or non-dividing state. Here, we describe a versatile in vivo gene knock-in methodology that enables the targeting of a broad range of mutations and cell types through the insertion of a minigene at an intron of the target gene locus using an intracellularly linearized single homology arm donor. As a proof-of-concept, we focused on a mouse model of premature-aging caused by a dominant point mutation, which is difficult to repair using existing in vivo genome-editing tools. Systemic treatment using our new method ameliorated aging-associated phenotypes and extended animal lifespan, thus highlighting the potential of this methodology for a broad range of in vivo genome-editing applications.

Keiichiro Suzuki, Mako Yamamoto, […]Juan Carlos Izpisua Belmonte. Other authors include Keiichiro Suzuki, Rupa Devi Soligalla, Emi Aizawa, Fumiyuki Hatanaka, Masakazu Kurita, Pradeep Reddy, Alejandro Ocampo, Tomoaki Hishida, Masahiro Sakurai, Amy N. Nemeth, Concepcion Rodriguez Esteban of Salk; Zhe Li, Christopher Wei and Kun Zhang of the University of California San Diego; Estrella Nuñez Delicado of Universidad Catolica San Antonio de Murcia; Jun Wu of University of Texas Southwestern Medical Center; Josep M. Campistol of the Hospital Clinic of Barcelona in Spain; Pierre Magistretti of the King Abdullah University of Science and Technology in Saudi Arabia; Pedro Guillen of the Clinica CEMTRO in Spain; Jianhui Gong, Yilin Yuan and Ying Gu of the BGI-Shenzhen in China; Guang-Hui Liu of the Chinese Academy of Sciences; and Carlos López-Otín from the Universidad de Oviedo in Spain.

The work was funded by the 2016 Salk Women & Science Special Award, the JSPS KAKENHI (15K21762 and 18H04036), the Takeda Science Foundation, The Uehara Memorial Foundation, the National Institutes of Natural Sciences (BS291007), The Sumitomo Foundation (170220), The Naito Foundation, The Kurata Grants (1350), the Mochida Memorial Foundation, The Inamori Foundation, the Guangdong Provincial Key Laboratory of Genome Read and Write (No. 2017B030301011), Guangdong Provincial Academician Workstation of BGI Synthetic Genomics (No. 2017B090904014), the Shenzhen Peacock Plan (No. KQTD20150330171505310), The Leona M. and Harry B. Helmsley Charitable Trust (2012-PG-MED002), the G. Harold and Leila Y. Mathers Charitable Foundation, the National Institutes of Health (R01HL123755 and 5 DP1 DK113616), The Progeria Research Foundation, The Glenn Foundation, KAUST, The Moxie Foundation, the Fundación Dr. Pedro Guillen, the Asociación de Futbolistas Españoles, and Universidad Católica San Antonio de Murcia (UCAM).

About the Salk Institute for Biological Studies:
Every cure has a starting point. The Salk Institute embodies Jonas Salk's mission to dare to make dreams into reality. Its internationally renowned and award-winning scientists explore the very foundations of life, seeking new understandings in neuroscience, genetics, immunology, plant biology and more. The Institute is an independent nonprofit organization and architectural landmark: small by choice, intimate by nature and fearless in the face of any challenge. Be it cancer or Alzheimer's, aging or diabetes, Salk is where cures begin. Learn more at: salk.edu.

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Aug 27 2019   Fetal Timeline   Maternal Timeline   News  

Neuron targeted using the SATI technology. CREDIT Salk Institute.

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