Mutational substitution
Edited genome helped Mice with congenital blindness
Polina Gershberg, Naked Science
The modified method of "planting" a healthy gene allowed to achieve results from gene therapy in cases in which it was previously impossible. It will be tested on humans in the coming years.
Scientists from the Tohoku University Graduate School of Medicine have proposed a new method of genetic therapy that allowed mice blind from birth to partially regain their eyesight. The authors published an article about the work done in Nature Communications (Nishiguchi et al., Single AAV-mediated mutation replacement genome editing in limited number of photoreceptors restores vision in mice).
The new method, tested by researchers, can become an alternative to the existing strategy of gene enhancement. Usually, with this method of gene therapy, a patient with a defective gene is, as it were, "planted" copies of a healthy gene.
In the case under consideration, this is a gene whose breakdowns can, in particular, lead to retinal dystrophy. An adeno-associated virus (AAV) is used to transport a healthy gene into the patient's tissues. But this method has a drawback: the virus can contain only a small healthy gene, and the vast majority of patients with defects in a larger gene cannot be treated with this method.
"To overcome this problem, we have developed <...> a therapeutic platform based on AAV, which allows local replacement of a mutant sequence with its healthy analogue, which can treat almost any mutation," says co–author Koji Nishiguchi.
This technique combines CRISPR-Cas9 technology with microhomological connection of the ends (breaking of DNA strands). Roughly speaking, this is a kind of genetic scissors and genetic glue, respectively. Researchers isolate the defect, remove it, putting a healthy area in its place, and restore the integrity of the entire "structure".
The difference between the concepts of gene therapy and mutational substitution therapy. In the first case, new copies of the entire healthy gene are added to the diseased cells. In the second, the mutated site is locally excised and replaced with a healthy sequence.
In a study by Japanese scientists, a new technique helped blind mice restore about 10% of photoreceptors. This led to improved photosensitivity and increased visual activity. The improvement in vision was about the same as the classical gene enhancement technique, which is not suitable for many patients, could give.
"The platform paves the way for the treatment of patients with mutations in larger genes, which make up the vast majority of patients with hereditary retinal degeneration. In addition, this approach can be used to treat almost any ocular and non–ocular hereditary conditions," says Nishiguchi.
Now the researchers plan to adapt a new technique to create a therapy that will help patients with retinitis pigmentosa – a disease that causes peripheral vision loss and vision problems at night. They will target common mutations among people who remain incurable through conventional gene therapy. Nishiguchi's team plans to conduct clinical trials by 2025.
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