Grant Backs CRISPR Therapy Research for Familial ALS

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

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

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

Similar to the editing system used by bacteria as a defense mechanism, CRISPR allows researchers to edit parts of the genome by adding, removing, or changing 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 obstacles for treating neurological conditions — reaching the central nervous system (CNS, the brain and spinal cord).

Typically, large molecules and microbes in the blood are prevented from reaching the CNS due to the presence of a highly selective, protective membrane called the blood-brain barrier.

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

“Our expertise in nanomaterials has provided a novel method to target and remotely modulate this barrier,” Zhenpeng Qin, PhD, a co-investigator of the project and an expert in the use of nanotechnologies to improve the treatment of brain diseases, said in a university 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. That causes the nanoparticles to generate gentle mechanical energy that opens the barrier temporarily, allowing the AAVs to pass through.

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

“Ideally, without the mutated gene, cells cannot make [ALS-associated] toxic proteins anymore, and the disease can’t develop,” Gao said.

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

“Our goal is to test in a small animal model the idea of using CRISPR to delete mutations as a one-time treatment for inherited ALS,” Gao said, adding that the team will first focus “on deleting one of the most common and well-characterized mutations” responsible for familial ALS.

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

Leonidas Bleris, PhD, a 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 modifications in the brain with single-cell precision.

“The possibilities are endless,” added Bleris, who also is an associate professor of bioengineering at UT Dallas and Fellow, Cecil H. and Ida Green Professor in Systems Biology Science.

Still, Gao cautioned that the project is just getting started and that it could take years before this type of CRISPR-based gene-editing approach becomes available to patients.

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