The new base editor is expected to treat genetic diseases

Parents of newborns may be aware of a metabolic disorder called phenylketonuria. In Switzerland, all newborns are screened for this genetic disease. Children with phenylalanine uremia have been found to have a special diet so that phenylalanine does not accumulate in the body. Excessive phenylalanine can delay mental and motor development. Children may suffer from severe mental disabilities if the genetic disease is not treated in a timely manner.
cause of this metabolic disorder is a mutation in the gene that encodes phenylalanine hydroxylase (Pah). This enzyme produced by liver cells metabolizes phenylalanine. This metabolic disorder is an "ever-chromosomal recessive" genetic disease: children who inherit a copy of a mutated gene from their mother and a copy of a mutated gene from their father develop the disease. So far, the disease is incurable.a new study,
researchers from the Federal Institute of Technology in Zurich, Switzerland, and the University of Zurich used a method to correct copies of two mutated genes in liver cells to cure the disease. They succeeded, at least in mice. The findings were published in the October 2018 issue of the journal Nature Medicine under the title "Treatment of a metabolic liver disease by vivo genome base editing in adult mice". The paper is co-authored by Professor Gerald Schwank of the Federal Institute of Technology in Zurich.
with the help of a CRISPR/Cas9 system reinforced with an enzyme, the researchers altered the base sequence in two copies of the mutated gene in adult mice. These corrected liver cells produced functional Pah enzymes, and the disease in these mice was cured.
this CRISPR/Cas9 system, which is reinforced by cytosine deaminase, binds to these two copies of genes that need to be corrected and opens the DNA double strands locally. Cytosine deaminase converts pathogenic DNA base pair C-G into base pair T-A present at corresponding genomic bits in healthy people. This corrects DNA base errors in the Pahase encoding gene.
in traditional CRISPR/Cas editing, induced DNA double-stranded fracture is the core element of genome editing. Double-stranded DNA is cut at a defined point, and then the cells try to repair the cut through a variety of mechanisms. If an exogenious matching DNA sequence is imported into a cell, it allows a specific repair mechanism to precisely repair a particular gene sequence. The problem is that most cells mainly use other DNA repair mechanisms, which produce additional unwanted mutations.more efficient genome editing
the researchers realized that the new genome editing tool was more effective than the traditional CRISPR/Cas9 method: up to 60 percent of all copies of mutated genes in mouse livers were corrected. This caused phenylalanine concentrations to drop to normal levels, and after treatment with this genome-editing tool, the mice showed no signs of this metabolic disorder.
in order to transfer the genetic code that encodes the new genome editing tool to liver cells, the researchers imported the required genes into adeno-related viruses (AAVs), which were then injected into the blood of mice. The virus infects liver cells, which in turn imports genes that encode this genome editing tool into liver cells.cure other metabolic
diseases, " says Schwank, "this method has great potential in the human body." "However, this study is only the first proof of concept. Preclinical studies are also needed in other animal models to test the efficacy and safety of this new genome editing tool when used in humans.
previous genome editing methods had only limited success in correcting target mutations directly in animals. Previously, Schwank explained, scientists had achieved only a few percent correction in the livers of adult mice. "In this new study, we've achieved an editing rate that's --- and so far no one has been able to do that."
Schwank believes the risk of this new genome editing tool is low. Using this editing tool in mouse models, the researchers looked for off-target mutations, i.e. mutations at places where mutations should not occur. However, they did not find any off-target mutations. Schwank hopes to study this more closely in subsequent studies. "The human liver is made up of billions of cells," Schwank stresses. In these cells, we don't want to induce any mutations that can cause cancer. "Tests are also needed to determine whether these researchers' use of the AAV virus as a carrier of genes that encode this editing tool will cause any adverse reactions.:
Lukas Villiger, Hiu Man Grisch-Chan, Helen Lindsay et al. Treatment of a metabolic liver disease by in vivo genome base editing in adult mice. Nature Medicine, October 2018, 24（10）：1519–1525, doi：10.1038/s41591-018-0209-1.
Huiyun Seo & Jin-Soo Kim. Towards therapeutic base editing. Nature Medicine, October 2018, 24 (10): 1493-1495, doi:10.1038/s41591-018-0215-3. (Bio Valley)