Army grant supports research into potential CRISPR therapy for familial ALS


Researchers at the University of Texas at Dallas (UT Dallas) received a U.S. Army Medical Research Acquisition Activity Award to advance their preclinical research on an innovative approach to gene editing based on CRISPR to treat one of the most common causes of familial amyotrophic laterality. sclerosis (ALS).

The nearly $ 650,000 two-year award went to the project’s principal investigator, Zhenghong Gao, PhD, a mechanical engineering researcher at UT Dallas’ Erik Jonsson School of Engineering and Computer Science, whose work focuses on nanotechnologies.

Some studies suggest that people who have served in the military are at greater risk of developing ALS than those who have no history of military service. However, there is no effective treatment to slow the progression of the disease.

Similar to the editing system used by bacteria as a defense mechanism, CRISPR allows researchers to modify parts of the genome by adding, removing or modifying specific sections of DNA.

With CRISPR-based treatments gaining increasing interest as potential therapies for familial ALS, which accounts for up to 10% of all cases, Gao’s approach has the potential to overcome one of the main barriers to treating ALS. neurological conditions – affecting the central nervous system (CNS, brain and spinal cord).

Typically, large molecules and microbes in the blood cannot reach the CNS due to the presence of a highly selective protective membrane called the blood brain barrier.

Since most gene therapies and gene editing approaches use modified and harmless adeno-associated viruses (AAVs) to transport and deliver a particular gene or the CRISPR machinery to cells, these treatments have a limited ability to achieve their target cells in the CNS.

“Our expertise in nanomaterials has provided a new method to remotely target and modulate this barrier,” said Zhenpeng Qin, PhD, co-investigator of the project and expert in the use of nanotechnologies to improve the treatment of brain diseases, in an academic press release.

The new approach uses light-sensitive gold nanoparticles that attach to the blood-brain barrier, after which the researchers apply short laser pulses. This causes the nanoparticles to generate soft mechanical energy that temporarily opens the barrier, allowing AAVs to pass through.

Once the virus enters target cells, the editing components of the CRISPR gene are released to correct the familial mutation causing ALS.

“Ideally, without the mutated gene, cells cannot [ALS-associated] more toxic proteins, and the disease cannot develop, ”Gao said.

“We hope that by improving the delivery of CRISPR therapy using our new barrier opening technology, we can significantly slow or even stop the progression of the disease,” Gao added.

“Our goal is to test in a small animal model the idea of ​​using CRISPR to suppress mutations as the sole treatment for inherited ALS,” Gao said, adding that the team will focus “on the first. removal of one of the “characterized mutations” responsible for familial ALS.

“If successful, we may be able to apply this new approach to remove or edit other mutations,” said the project leader. He also noted that in the long term, this type of approach can also be used to treat other neurodegenerative diseases, such as Parkinson’s disease, Alzheimer’s disease and Huntington’s disease.

Leonidas Bleris, PhD, co-principal investigator of the project at UT Dallas and a pioneer in gene editing, said that “CRISPR is an incredibly powerful tool” and that the team is “optimistic that in the near future, we will be able to perform surgical changes in the brain with single cell precision.

“The possibilities are endless,” added Bleris, who is also associate professor of bioengineering at UT Dallas and associate, Cecil H. and Ida Green, professor of systems biology science.

Still, Gao warned that the project is only just beginning and it could be years before this type of CRISPR-based gene editing approach becomes available to patients.

The multidisciplinary team also includes two ALS experts from Northwestern University Feinberg School of Medicine in Chicago, Illinois: Han-Xiang Deng, MD, PhD, and Evangelos Kiskini, PhD.

Marta Figueiredo holds a master’s degree in evolutionary and developmental biology and a doctorate in biomedical sciences from the University of Lisbon, Portugal. His research focuses on the role of several signaling pathways in the embryonic development of the thymus and parathyroid glands.

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Inês holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she specialized in the biology of blood vessels, blood stem cells and cancer. Previously, she studied cellular and molecular biology at the Universidade Nova de Lisboa and worked as a research fellow at the Faculdade de Ciências e Tecnologias and at the Instituto Gulbenkian de Ciência. Inês currently works as a science editor, striving to deliver the latest scientific advances to patient communities in a clear and precise manner.

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