Recently, in a research report titled "In vivo base editing rescues Hutchinson–Gilford progeria syndrome in mice" published in the international journal Nature, scientists from the United States MIT and the Broad Institute reported a landmark gene therapy Milestone research results. The researchers said that a new type of CRISPR technology may bring revolutionary changes to gene therapy, thereby bringing new hope for the treatment of patients with genetic diseases.
In the article, researchers have conducted research on childhood progeria, which is a genetic disease that causes rapid aging of children. At present, the second generation of CRISPR gene editing technology developed by scientists-base editing (base editing) is already in development. Successful tests have been carried out in the mouse body. With the help of this technology, researchers may eventually correct human life-long genetic diseases, including childhood progeria.
A rare but deadly disease
Prior to the breakthrough in this research, researcher Francis Collins had conducted years of research on childhood progeria. Children with progeria mutations often have normal intelligence, but will show early signs of general aging, including hair loss and hearing loss; by ten After a few years, the child will look very old. Few of these adolescent patients can live beyond the age of 13; in 2003, researchers found that childhood progeria is caused by a mutation in a gene encoding Lamin A protein, which plays a key role in the nucleus. Structural role.
Image source: Shutterstock
Many people carry multiple gene mutations, but since we usually have two gene copies, one from the father and one from the mother, it is often enough to have a good copy of the gene. But Lamin A's progeria mutation is different. Although there may be a good copy of the gene in the patient's body, the mutant copy will produce a toxic product and mess things up. This type of mutation is called " Dominant negative mutation". The ideal solution is to use CRISPR technology to correct the copy of the mutation. With this gene editing tool, scientists can direct a pair of molecular scissors to any part of the genome. Unfortunately, the first-generation CRISPR technology does He is good at cutting genes, but does not have the accuracy and efficiency to correct Lamin A mutations.
Complications of large-scale cell editing
CRISPR scissors are good at finding targets and cutting, but the subsequent reconstruction surgery is done by cells, and this does not guarantee that every cell will happen. In the laboratory, researchers usually only need to correct a few cells to fix it, and then further study it in a petri dish. But in the human body, we need to correct most cells, or even all cells; it may be meaningless to correct the progeria mutations of only 5 cells on the patient's finger, and let other cells in the body not be repaired.
This is where the researcher David Liu's work in base editing technology is crucial. He discovered the limitations of CRISPR technology early on and began to develop molecular machines that can only operate as targeted molecular scissors. He started with naturally occurring enzymes that can change one chemical base in the genetic code to another, such as A to G or C to T. Subsequently, the researcher Liu modified these enzymes to make them more precise and fused them with CRISPR to develop a fusion protein called a base editor. Because CRISPR technology is good at reading DNA and finding targets, the research Can effectively transport the editor to the gene locus that needs to be changed.
But it needs to be emphasized that the researcher Liu deliberately developed a base editor so that it can change bases, but it no longer cuts DNA molecules like CRISPR scissors. This is very important, because cutting DNA will increase more. The risk of a large chromosome loss, which may damage the cell.
Differences between mice and men
The researchers knew that they had to implant base editors into the cells of mice with progeria to cure the disease, so they used a hollowed-out virus as a transport vector. In the article, the researchers used a vector based on adeno-associated virus (AAV), which is one of the smallest viruses that does not cause any known diseases. Researcher Collins et al. packaged AAV virus particles with genes encoding related base editing enzymes, and then transported them to mice. The treated mice can basically avoid the occurrence of diseases and become healthy and small. Rats make no difference.
Of course, all of this happens in mice, and humans are larger; researchers don’t know how difficult it will be to upgrade this gene editing machine to humans, but anyway, they have moved forward. It has taken an important step and demonstrated the possibility of using it in the body of mice. Gene editing CRISPR tools may be an opportunity for experts who are committed to using gene therapy and families with progeria to be cured of their dreams to come true; work in this area has just begun, and later scientists need to go deeper. The research to continue to advance. (Bioon.com)
Reference materials:
【1】Koblan， L.W.， Erdos， M.R.， Wilson， C. et al. In vivo base editing rescues Hutchinson–Gilford progeria syndrome in mice. Nature 589， 608–614 (2021). doi：10.1038/s41586-020-03086-7
【2】New CRISPR technology could revolutionize gene therapy， offering new hope to people with genetic diseases by Merlin Crossley， The Conversation