RARE Daily

Scientist Develop Novel Gene Editor to Correct CF and Other Mutations

March 16, 2021

Rare Daily Staff

A team of researchers from the Agency for Science, Technology and Research’s Genome Institute of Singapore has developed a CRISPR-based gene editor, C-to-G Base Editor, to correct mutations that cause genetic disorders.

Their research was published in Nature Communications on 2 March 2021.

Globally, one in seventeen people has some type of genetic disorder with approximately 450 million people affected worldwide. Mutations responsible for these disorders can be caused by multiple mutagens – from sunlight to spontaneous errors in your cells. The most common mutation by far is the single-based substitution, in which a single-base in the DNA (such as G) is replaced by another base (such as C). Countless cystic fibrosis patients worldwide have C instead of G, leading to defective proteins that cause the genetic disease. In another case, replacing A with T in hemoglobin causes sickle cell anemia.

To fix these substitutions, the team at A*STAR’s Genome Institute of Singapore (GIS) at invented a CRISPR-based gene editor that precisely changes the defective C within the genome to the desired G. This C-to-G base editor (CGBE) invention opens up treatment options for approximately 40 per cent of the single-base substitutions that are associated with human diseases such as cystic fibrosis, cardiovascular diseases, musculoskeletal diseases, and neurological disorders.

The CGBE editor advances the widely adopted CRISPR-Cas9 technology to enable molecular surgery on the human genome. While it is routinely used to disrupt target genes, but CRISPR-Cas9 is inefficient when a precise change to particular sequence is desired. The CGBE editor resolves a key aspect of this challenge by enabling efficient and precise genetic changes. CGBE consists of three parts: a modified CRISPR-Cas9 will pinpoint the mutant gene and focus the entire editor on that gene; a deaminase (an enzyme that removes the amino group from a compound) will then target the defective C, and mark it for replacement; and finally, a protein will initiate cellular mechanisms to replace that defective C with a G. This enables a previously unachievable direct conversion from C to G, correcting the mutation and, consequently, treating the genetic disorder.

“The CGBE gene editor is a ground-breaking invention that for the first time, directly converts C to G in genes, which potentially opens up treatment avenues for a substantial fraction of genetic disorders associated with single-nucleotide mutations,” said Chew Wei Leong, senior research scientist at GIS.

For now, the editor is being tested in disease models for effectiveness and safety, but it and other novel precision genome editing tools could hold promise for delivering effective cures for monogenic diseases.

Photo: Chew Wei Leong, senior research scientist at GIS

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