A new study shows that CRISPR therapy can reduce fats without turning over DNA. The article published on December 13, 2018 ScienceUC San Francisco researchers describe how the modified CRISPR version was used to drive some genes and prevent severe obesity in mice with genetic mutations that cause extreme weight gain. It is important that the researchers achieved long-term weight control without creating a single genome editing.
One copy of the mutation is accompanied by many human diseases
Although the human genome has two copies of each gene in an individual, one from each parent, scientists know at least 660 genes, where a mutation in one copy can lead to diseases, some of which are devastating. One of the following conditions is severe obesity, which the authors of the new study used as a model to develop a new therapeutic approach to the treatment of these disorders.
Mutations in one copy of SIM1 or MC4R – two genes critical to regulating hunger and satiety – are the most commonly observed mutations in particularly obese individuals. If both copies of these genes are working, people are usually able to manage their diets. But mutations can make one copy non-functional, forcing the body to rely only on one copy of the work, which in itself does not sufficiently confirm the sensation, leaving the offended individuals with an unrestrained appetite. As a result, they can not control their diet and are largely obese. However, recent advances in CRISPR technology can offer a solution.
"We thought that if we could increase the dose of the current functional gene copy, we could prevent many human diseases in people suffering from these mutations," said Nadav Ahituv, Ph.D., Professor of Bioengineering and Therapeutics and a new study. "We could do this with the new CRISPR technology developed right here at UCSF."
CRISPR activates appetite suppressing genes
The technology concerned is to activate CRISPR (a). Developed by the UCSF Laboratory Jonathan Weissman, Ph.D., Professor of Cellular and Molecular Pharmacology, CRISPR differs from conventional CRISPR, since this does not mean genome excision. It saves the CRISPR control system that can be programmed home in a specific DNA sequence, but replaces the molecular scissors with the volume control button. When CRISPR detects its goal, it intensifies the activity of this gene. No corrections have been made.
Recognizing its potential, researchers created CRISPR systems that selected sequences that govern the operation of SIM1 or MC4R. They used a virus-infusion system to implement these CRISPRra constructs in brain famine control regions in mice that were genetically engineered to produce only one functional, either gene copy.
Mice that received CRISPR constructs produced more SIM1 or MC4R than those who did not. In addition, the amounts were comparable to the mice that normally produce two copies of these genes. Most importantly, the increased dose was enough to prevent mice from becoming obese.
"The results were dramatic. Mice lacking a single copy of the SIM1 gene received CRIPR injections after four weeks and maintained healthy body weight, such as normal mice. Mice not receiving CRISPR injections could not stop eating, began to gain weight at 6 weeks of age, and until "When they were 10 weeks old, they were seriously obese for a regular diet," said Navneet Matharu, a doctor, researcher at Ahituv Laboratory and lead author in a new study.
CRISPR-treated mice were 30 to 40 percent lighter than their virgin counterparts. The effect was also lasting. Researchers monitor mice for ten months – a significant proportion of the mouse's normal lifespan – and found that those receiving one CRISPR treatment maintained a healthy weight during their monitoring.
"These results show that CRISPR can be used to increase the dose of genes due to illnesses caused by missing copies potentially curing certain forms of obesity, as well as hundreds of other diseases," Mathara said.
CRISPR can overcome genetic constraints
Researchers believe that they could achieve similar results using CRISPR to edit the genomes of these mice, but they claim that CRISPR has several advantages over the standard version of gene transcription technology.
"For therapeutic purposes, CRISPR can be better than conventional CRISPR and it solves many of the challenges associated with ongoing genetic changes and has the potential to treat various genetic diseases, for which gene regeneration is not an option," said Christian Vaisse, MD, PhD, Vera M. Long assigned the chair of diabetes research at UCSF and co-author of the study.
Although CRISPR targets targeted DNA sequences, adjacent target effects have been observed. With conventional CRISPR, this can lead to accidental but permanent changes in the genome with potentially harmful results. However, the non-target effect associated with CRISPA is likely to be detrimental as there is no permanent change. In fact, the new study shows that using CRISPR to target promoters and amplifiers – without encoding DNA sequences that control when and where the gene is turned on – seems to prevent target exposure beyond the target, while limiting the desired results to specific tissues of interest.
Researchers also note that CRISPR can be used to treat other types of genetic diseases. Diseases resulting from so-called "microdeletions," a term that counteracts the loss of large chromosome segments that span millions of nucleotides and multiple genes, are currently too high for normal CRISP to be corrected. In such cases, CRISPR can be used to compensate for deletion by increasing the activity of several genes in an unaffected copy of the chromosome. And in cases where the gene completely disappears, CRISPR can activate another gene with a similar function to compensate for the missing gene, researchers say.
"Although this particular study focused on obesity problems, we believe that our system can be applied to any situation in which only one functional gene copy leads to the disease," said Ahituv. "Our method demonstrates tremendous therapeutic potential for many diseases, and we show that we can benefit from these without any changes in the genome."