Team develops gene-editing strategy that may be safer, more efficient
Technique bypasses some major limitations of traditional approaches
A team of U.S. researchers has developed a new gene-editing strategy that could make the approach safer and more efficient for treating certain diseases, such as hemophilia.
In preclinical studies, the gene-editing technique was shown to enable fast and efficient delivery of healthy genetic material to cells, while bypassing some of the major limitations of traditional gene-editing approaches.
“This could lead to faster and more affordable treatments for a wide range of diseases, potentially impacting hundreds of conditions with a single faulty gene,” Jesse Owens, PhD, assistant professor at the University of Hawai’i at Manoa and the study’s senior author, said in a university press release.
The study, “Directed evolution of hyperactive integrases for site specific insertion of transgenes,” was published in the journal Nucleic Acids Research.
In most cases, hemophilia is caused by genetic mutations that lead to the insufficient production or activity of important blood clotting proteins. This, in turn, leads to the disease’s hallmark symptoms of excessive, prolonged, or spontaneous bleeding episodes.
Gene editing modifies person’s own DNA to address underlying cause of disease
Gene editing is a therapeutic strategy of significant interest for hemophilia and other diseases with a known genetic cause. With gene editing, a person’s own DNA is modified in ways that are expected to address the underlying cause of the disease.
For example, hemophilia A patients have mutations in the F8 gene that encodes a blood clotting protein called factor VIII (FVIII). A gene-editing approach for these patients might aim to insert a healthy version of F8 into their cells, thereby increasing the production of functional FVIII.
Traditional gene-editing approaches involve special enzymes called nucleases that make cuts through both strands of a person’s DNA. Natural cellular mechanisms then kick in to repair the damage. While that’s happening, scientists can make other manipulations to remove, add, or alter parts of the gene. The most well known gene-editing system is called CRISPR-Cas9.
However, traditional gene-editing strategies have a significant drawback: they can sometimes cause unintended damage to healthy DNA. Moreover, it can be very difficult to efficiently insert large amounts of genetic material, such as an entire gene.
Now, scientists have developed a way to help overcome these limitations and make gene-editing therapy safer and more efficient.
Process uses engineered enzyme to insert therapeutic genes into DNA
The process employs an engineered enzyme called “super-active integrase” that’s able to precisely and efficiently insert therapeutic genes into a person’s DNA with success rates of up to 96%.
Notably, the approach avoids double-stranded DNA cuts, which is where unintended damage can happen with traditional approaches.
Instead, special attachment sites are targeted to certain parts of the genome. The integrase enzymes help guide the gene that needs to be inserted to those sites, where it facilitates their integration into a person’s DNA.
“It’s like having a ‘paste’ function for the human genome,” Owens said.
In the study, the scientists showed proof of concept of their approach by demonstrating they could efficiently insert a large gene encoding von Willebrand Factor, a blood clotting protein, into cells.
Ultimately, the approach could possibly help insert other blood clotting genes, like those involved in hemophilia, as a therapeutic strategy for patients.
It’s like having a ‘paste’ function for the human genome.
Implications of findings may extend beyond gene editing
The researchers indicated that the implications of the findings may also extend beyond gene editing, with the possibility to speed up the development of other advanced treatment modalities, such as antibody-based therapeutics.
They’ll continue to explore this possibility in upcoming research projects. Owens recently founded a nonprofit called the Hawaii Advanced Genetic Medicine Foundation, which will support genetic engineering research in the state.
“We envision that this highly efficient technology will be tailored to diverse research tools and future therapies,” the researchers wrote.
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