The First Use of CRISPR to Treat a Genetic Disease in a Live Patient

By Ryan Hylton

Basic concept of the CRISPR-Cas9 system. Photo Credit: Vox/Javier Zarracina

At least 6,000 human diseases are caused by heritable genetic mutations1. A long-time dream of physicians and patients alike has been to specifically treat these diseases by manipulating the genetic code in affected patients. This dream became one step closer to reality when last month, researchers injected CRISPR, the most promising of existing genetic engineering tools, into a live adult for the first time2.

The goal of the study was to cure the most common form of genetic blindness, Leber congenital amaurosis type 10 (LCA10)3. This condition can occur as a result of multiple mutations, the most common of which is a point mutation that results in the expression of an incorrectly spliced version of the CEP290 gene4. The function of the protein coded for by CEP290 is not fully understood, however, it appears to play a role in the structure and function of cilia. Cilia are appendages that extend from the surface of many cell types and have a diverse array of functions. Sensory cilia play an important role in phototransduction in the outer segment of photoreceptors in the retina5. Therefore, the aforementioned CEP290 mutation is thought to result in dysfunctional retinal ciliaand affected patients often lose most, if not all, of their ability to see in the early years of their life6. Researchers hope to correct the causative mutation by using an adenoviral vector to deliver the CRISPR-Cas9 system into the retina.

The procedure is relatively simple. First, a surgeon creates an incision in the eye. Next, through that incision a few droplets of the CRISPR-equipped adenoviruses are injected onto the patient’s retina2. The CRISPR-Cas9 system itself is adapted from a natural antiviral defense mechanism found in bacteria (see Figure 1). A short guide RNA sequence is generated that complements a target DNA sequence. Once the guide RNA attaches to the correct site, the enzyme Cas9 cuts the DNA. This cut is then repaired by the cell’s endogenous DNA repair machinery7. Often times, a “repair template” DNA sequence is also added so that the repaired genomic DNA has a specific, desired sequence8. Using this technology, researchers hope to fix the CEP290 mutation and produce a properly spliced RNA transcript. This should result in a fully functioning CEP290 protein and hopefully restore vision for these patients. It is too early to tell if this treatment will be effective however, researchers plan to monitor patient progress over the next few months2.

There is some initial precedent that gives us hope for the CRISPR treatment of LCA10. Although this is the first occurrence of CRISPR being delivered into a living human, this gene engineering technology has recently been used in clinical trials for other diseases, such as b-thalassemia and sickle cell anemia in which cells were taken from patients and the DNA was manipulated in the laboratory before the cells were injected back into the patient2. One particularly hopeful example comes from a woman suffering from sickle cell anemia. Last year, stem cells from her bone marrow were removed and the genome of the cells were manipulated by CRISPR prior to being reintroduced into her body9. The goal of this procedure was to induce the expression of fetal hemoglobin, a protein that is only expressed temporarily, before and shortly after birth. Fetal hemoglobin’s oxygen-carrying capacity is evidently as efficient as normal adult hemoglobin. In the case of sickle cell anemia, the adult hemoglobin is abnormal, hence replacing adult hemoglobin with fetal hemoglobin should restore normal function to the red blood cells. After a few months, 46.6% of the hemoglobin in the patient’s blood is of the fetal variety, and 94.7% of her blood cells possess fetal hemoglobin9. Her doctors caution that it is too early to consider this result the miracle cure everyone hopes for, but this is the start to a very promising therapeutic avenue.

In the case of LCA10 and most other genetic disorders, the affected cells cannot be removed and genetically manipulated outside of the body. Nonetheless, if the current study shows that manipulating the genomes of specific cells in the body is possible through the CRISPR-Cas9 adenoviral system, then it opens the door for an abundance of potential therapeutic applications for numerous other genetic conditions. As of now, there are many genetic conditions that have no known cure, but CRISPR might be the solution.  


  5. Bujakowska KM, Liu Q, Pierce EA. Photoreceptor cilia and retinal ciliopathies. Cold Spring Harbor Perspectives in Biology. 2017;9:a028274

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