CRISPR technology offers the promise to cure any human genetic disease. Which are the candidates to be the first one?

CRISPR-Cas9 was first used as a gene editing tool in 2012. In just a few years, the technology has exploded in popularity thanks to its promise of making gene editing much faster, cheaper and easier than ever before.

CRISPR has already changed the way scientists do research. But what everyone is expecting, either with excitement or fear, is its use in humans. In theory, CRISPR technology could let us edit any genetic mutation at will, curing the disease it causes. In practice, we are just at the beginning of the development of CRISPR as a therapy and there are still many unknowns.

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But if you had at least a chance to cure any genetic disease, which one would it be? These are seven diseases that scientists are already tackling with the help of CRISPR-Cas9, and which could eventually become the first conditions to ever be treated with this revolutionary technology.

1. Cancer

The first applications of CRISPR could be in cancer. Indeed, one of the first and most advanced CRISPR clinical trials, which is currently running in China, is testing the potential of the gene editing tool to treat patients with advanced cancer of the esophagus.

The treatment being tested at the Hangzhou Cancer Hospital starts with the extraction of immune T cells from the patient. Using CRISPR, the cells are modified to remove the gene that encodes for a protein called PD-1 — some tumors are able to bind to this protein on the surface of immune cell and instruct them not to attack. The modified cells are then reinfused into the patient with a higher capacity to attack cancer cells.

So far, at least 86 people with different forms of cancer have been treated with CRISPR in China. In the US, another CRISPR trial, with the first patients treated in April 2019, also targets cancer. Scientists at the University of Pennsylvania are using CRISPR to remove PD-1 as well as to change a molecule on the surface of immune cells to make them find and attack tumors.

2. Blood disorders

The first CRISPR trial in Europe and the US, which enrolled its first patient in February this year, aims to treat beta-thalassemia and sickle cell disease, two blood disorders that affect oxygen transport in the blood. The therapy, developed by CRISPR Therapeutics and Vertex Pharmaceuticals, consists in harvesting bone marrow stem cells from the patient and using CRISPR technology to make them produce fetal hemoglobin, a natural form of the oxygen-carrying protein that binds oxygen much better than the adult form.

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Before the trial started, the FDA put it on hold in the US to clear out some safety questions. A few months later, the hold was lifted and the treatment was given fast track designation for both conditions.

Hemophilia is another blood disorder that CRISPR technology could tackle. CRISPR Therapeutics is working with Casebia on an in vivo CRISPR therapy where the gene editing tool is delivered directly to the liver.

3. Blindness

CRISPR is a great candidate to treat genetic blindness. Many hereditary forms of blindness are caused by a specific mutation, making it easy to instruct CRISPR-Cas9 to target and modify a single gene.

In addition, the eye is an immunoprivileged part of the body, meaning that the immune system’s activity is limited there. This becomes an advantage in sight of the concerns regarding the possibility that CRISPR could induce immune reactions against it, which would block its activity and derive into side effects.

Editas Medicine is working on a CRISPR therapy for Leber congenital amaurosis, the most common cause of inherited childhood blindness, for which there is no treatment. The company aims to target the most frequent mutation behind the disease, using CRISPR to restore the function of light-sensitive cells before the children lose sight completely.

4. AIDS

There are several ways CRISPR technology could help us in the fight against AIDS. One is using CRISPR to cut the DNA of the HIV virus out of its hiding place in the DNA of immune cells. This approach could be used to attack the virus in its hidden, inactive form, which is what makes it impossible for most therapies to completely get rid of the virus.

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Another approach could make us resistant to HIV infections. Certain individuals are born with a natural resistance to HIV thanks to a mutation in a gene known as CCR5, which encodes for a protein on the surface of immune cells that HIV uses as an entry point to infect the cells. The mutation changes the structure of the protein so that the virus is no longer able to bind to it.

This approach was used in a very controversial case in China last year. CRISPR-Cas9 was used to edit human embryos to make them resistant to HIV infections. The experiment caused outrage among the scientific community, with some studies pointing out that the ‘CRISPR babies’ might be at a higher risk of dying younger. The general consensus seems to be that more research is needed before this approach can be used in humans.

5. Cystic fibrosis

Cystic fibrosis is a genetic disease that causes severe respiratory problems. Although there are treatments available to deal with the symptoms, the life expectancy for a person with this disease is only around 40 years. CRISPR technology could help us get to the origin of the problem by editing the mutations that cause cystic fibrosis, which are located in a gene called CFTR.

Researchers have proven that it is possible to use CRISPR in human lung cells derived from patients with cystic fibrosis and fix the most common mutation behind the disease. The next step will be testing it in humans, which both Editas Medicine and CRISPR Therapeutics plan to do.

However, cystic fibrosis can be caused by multiple different mutations in the CFTR gene, meaning that different CRISPR therapies will have to be developed for different genetic defects. Editas has stated that it will be looking at the most common mutations, as well as some of the rare ones for which there is no treatment.

6. Muscular dystrophy

Duchenne’s muscular dystrophy is caused by mutations in the DMD gene, which encodes for a protein necessary for the contraction of muscles. Children born with this disease suffer progressive muscle degeneration, and there is currently no treatment available beyond palliative care.

Research in mice has shown CRISPR technology could be used to fix the multiple genetic mutations behind the disease. Last year, a group of researchers in the US revealed an innovative method that, instead of fixing each mutation individually, used CRISPR to cut at 12 strategic ‘mutation hotspots’ covering the majority of the estimated 3,000 different mutations that cause this muscular disease. A company called Exonics Therapeutics was spun out to further develop this approach.

Editas Medicine is also working in a CRISPR therapy for Duchenne’s muscular dystrophy. It is also following a broader approach where instead of fixing mutations, CRISPR removes whole sections of the mutated protein, which makes the protein shorter but still functional.

7. Huntington’s disease

Huntington’s disease is a neurodegenerative condition with a strong genetic component. The disease is caused by an abnormal repetition of a certain DNA sequence within the huntingtin gene. The higher the number of copies, the earlier the disease will manifest itself.

Treating Huntington’s could be tricky, as any off-target effects of CRISPR in the brain could have very dangerous consequences. To reduce the risk, scientists are looking at ways to tweak the gene editing tool to make it safer.

Researchers in the US have developed KamiCas9, a version of CRISPR-Cas9 that includes a “self-destruct button”. A group of Polish researchers has opted for pairing CRISPR-Cas9 with an enzyme called nickase to make the gene editing more precise.

It’s difficult to predict the outcome of these early efforts to use CRISPR as a therapy, but as these first attempts progress, more and more indications will certainly be added to the list. One of the biggest challenges to turn this research into real cures is the many unknowns regarding the potential risks of CRISPR therapy. Some scientists are concerned about possible off-target effects, immune reactions to the gene editing tool, or the fact that it could increase the risk of cancer. But only time will tell whether these challenges can be surmounted or not.

Images via NIH /Flickr; Shutterstock. This article was originally published on June 2018 and has since been updated with the latest developments in CRISPR research.