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Gene Repair Offers Hope and Challenges

Publication date: 14 Dec 2018

Many rare disorders originate from gene mutations— typos in the DNA that disrupt normal cellular functions.  What if it were possible to fix errors in DNA sequences that cause genetic diseases? Would this permanently cure the disease? Can genes be mended as easily as jeans? Not yet, but interestingly, the concept is not beyond the realm of possibility.

In recent years, scientists have learned how to manipulate a precise DNA cutting mechanism found in bacteria called CRISPR. This system is used by microorganisms to defend themselves from foreign DNA by comparing invading sequences to those stored on a genetic “wanted list." If there’s a match, the DNA is cut. By co-opting this bacterial machinery, DNA sequences of any type, including those of disease-causing genes, can be cut. Once cut, DNA repair mechanisms can be harnessed to insert a corrected sequence and the genetic patch is completed.

Early work is now being done to use this technology to treat human disease. One such effort at Stanford University targets sickle cell anemia, a disease caused by a single A to T letter change in the gene encoding beta-hemoglobin. Patients experiencing full-blown symptoms of sickle cell disease have two copies of the defective gene— the repair of just one of these copies may be potentially curative. However, the approach is complex. To minimize unwanted side effects, the patient’s own blood stem cells are targeted for the treatment. First, the bacterial CRISPR genes have to be introduced to the cells to set-up the DNA-cutting and repair machinery. Next, the cut target guide and corrective gene sequences are added to allow the repair to take place. Since the process is not 100% efficient, those cells that have the desired repaired gene need to be screened and selected. These stem cells are then grown in laboratory to larger numbers that can then be returned to the patient where they can take up residence in the bone marrow and produce healthy red blood cells. The goal is to have patients become symptom-free for life. Clinical trials of this approach may begin as early as next year.

Alternatively, many genetic diseases are caused by a dominant defective gene, where a patient may have a copy of the disease-causing gene as well as a normal version. In this case, the protein produced from the defective gene prevents the protein from the normal gene from exerting its proper function. Here, the strategy could be to inactivate the defective gene by targeted cutting using CRISPR, thereby allowing the remaining normal gene to do its regular job. Such an approach is being explored at UC San Francisco for Charcot-Marie-Tooth disease, a degenerative muscle disorder, and for Best disease, an eye disorder. Laboratory studies using patient derived cells are underway, although much work still needs to be done before they can be used therapeutically.

As with any new technology, there are risks and ethical questions that must be addressed. While CRISPR gene editing can be very precise in theory, there are concerns that it can cause unwanted DNA damage due to non-specific cutting leading to inadvertent side effects. On an ethical level, most would accept the use of CRISPR on non-germ line cells for treatment of an active otherwise incurable disease. On the other hand, the potential genetic editing of humans for non-disease related purposes or of reproductive cells and embryos enters uncharted territory. Recent reports of CRISPR-treated embryos in China have provoked much controversy. Beyond a doubt, we are on the cusp of the dawn of a new field of medicine— genetic surgery, which offers tremendous hope in the treatment of rare disorders while posing enormous unprecedented challenges.