CRISPR-based obesity treatment shows promise for other diseases

A recent study by Nadav Ahituv, PhD, showed that obesity caused by a gene mutation could be treated in animal models using a modified version of the CRISPR gene editing system, called CRISPRa. Developed at UC San Francisco, CRISPRa (a for activation) doesn’t cut DNA like its CRISPR forerunner but instead prods a chosen gene to produce more protein than it normally would.

Ahituv is a faculty member in the Department of Bioengineering and Therapeutic Sciences, a joint department of the UCSF Schools of Pharmacy and Medicine.

Ahituv’s experiment targeted two genes involved in controlling appetite: SIM1 and MC4R. Most people have two operational copies of each of these genes in their DNA. But in some people, one of these copies is damaged. As a result, people with the broken gene are constantly hungry and develop obesity.

In the study, published in Science on December 13, 2018, Ahituv used CRISPRa to coax a single functional copy of either SIM1 or MC4R to produce extra protein to regulate hunger in mice with a dysfunctional copy of either gene. The remaining gene produced enough of the missing protein that mice that received the treatment did not become obese.

Ahituv spoke to the School of Pharmacy’s editorial director, Grant Burningham, about the research and the possibility of treating other haploinsufficient diseases, the term for disorders caused by having one broken copy in a matching pair of genes.

Burningham: How does CRISPRa work and how is it different than regular CRISPR?

Ahituv: CRISPRa uses what’s called a dead Cas9, meaning the part of the CRISPR system that actually cuts DNA has been disabled, so CRISPRa can only bind to DNA. We can use the CRISPRa system as a courier truck to deliver an activator to a specific part of the genome, forcing a specific gene to make more RNA product and therefore more protein.

The advantage of CRISPRa for human therapies is that it doesn’t make permanent edits to the genome. There are no genetic scars and, as such, there is less of a danger of off-target effects.

Burningham: How much of obesity is caused by mutations like the ones in your experiment?

Ahituv: Humans generally have two copies of each gene, one from our mom and one from our dad. For a lot of these genes, one broken copy won’t affect our health. But in about 660 genes, mutations that completely kill the function of one copy will cause disease. The type of obesity we looked at in this study is one example.

We looked at two genes involved in controlling appetite: SIM1 and MC4R. If you look at the top 1% of chronic obesity cases, about 2% of those subjects have a SIM1 mutation and 5% have an MC4R mutation. People with these mutations always feel hungry, and they end up obese. They often die in their fifties as a result of complications that come with severe obesity.

Burningham: Did the mice have side effects from the treatment?

Ahituv: No, we didn’t see any difference between the two groups in terms of abnormalities or deaths. But we also didn’t go too deep, to look at things like immune response or inflammation. There’s still a lot of work to do.

Burningham: You actually injected the treatment into the mouse brain. Is that too much to ask for a human treatment?

Ahituv: There are already some treatments that require injections in the brain. That might be a questionable treatment to give someone for obesity, but other haploinsufficient diseases, where one gene isn’t working but one is, are quite severe. It may be that this type of approach will work for other diseases that can be caused by haploinsufficiency. That includes epilepsy and other debilitating neurological diseases. In those cases, a brain injection would be something to consider.

Burningham: Why did you start with obesity?

Ahituv: We wanted something that would be easy to measure, so even minor changes with the gene we were targeting would be easy to quantify. Body weight is easy to measure. We are also using this treatment as a tool to learn about the disease. It will be interesting to see when we can intervene in the disease and still get results. We started treating the mice before they developed the symptoms of obesity, and now we’re curious if we could reverse the symptoms with the treatment once they’ve already appeared. We could also try to treat different neurons in the brain. That will also teach us a lot about how the disease works.

Burningham: Thank you for talking to me, it will be exciting to see where this research goes.

Ahituv: Thanks for taking the time.


School of Pharmacy, Department of Bioengineering and Therapeutic Sciences, PharmD Degree Program

About the School: The UCSF School of Pharmacy aims to solve the most pressing health care problems and strives to ensure that each patient receives the safest, most effective treatments. Our discoveries seed the development of novel therapies, and our researchers consistently lead the nation in NIH funding. The School’s doctor of pharmacy (PharmD) degree program, with its unique emphasis on scientific thinking, prepares students to be critical thinkers and leaders in their field.