CRISPR gene editing reveals new therapeutic approach for blood disorders

August 15, 2016
DNA
Credit: NIH

An international team of scientists led by researchers at St. Jude Children's Research Hospital has found a way to use CRISPR gene editing to help fix sickle cell disease and beta-thalassemia in blood cells isolated from patients. The study, which appears online today in Nature Medicine, provides proof-of-principle for a new approach to treat common blood disorders by genome editing.

"Our approach to is informed by the known benefits of hereditary persistence of ," said Mitchell J. Weiss, M.D., Ph.D., chair of the St. Jude Department of Hematology and one of the study's lead authors. "It has been known for some time that individuals with genetic mutations that persistently elevate fetal hemoglobin are resistant to the symptoms of sickle cell disease and beta-thalassemia, genetic forms of severe anemia that are common in many regions of the world. We have found a way to use CRISPR gene editing to produce similar benefits."

Fetal and adult hemoglobin are two different molecular forms of the essential oxygen-carrying molecule in . Hemoglobins are made up of different combinations of four molecular subunits. Sickle cell disease and beta-thalassemia are caused by mutations in a gene encoding an adult-expressed subunit termed "beta." Disease becomes apparent after birth as the levels of take hold and levels of fetal hemoglobin decline. These mutations can affect the survival of red blood cells and inhibit oxygen delivery to tissues, causing impaired function of different organs with devastating consequences for patients. Fetal hemoglobin lacks beta subunits and has gamma subunits instead. Thus, beta-thalassemia or sickle cell disease-associated mutations, which impair the production or function of the beta subunit, do not cause problems with fetal hemoglobin, which can transport oxygen effectively in adults.

Experts have known for some time that inhibiting or reversing "gamma-to-beta" switching of hemoglobin subunits can raise levels of fetal hemoglobin in adults and significantly ameliorate the debilitating symptoms of beta-thalassemia or sickle cell disease.

"Our work has identified a potential DNA target for genome editing-mediated therapy and offers proof-of-principle for a possible approach to treat sickle cell and beta-thalassemia," added Weiss. "We have been able to snip that DNA target using CRISPR, remove a short segment in a "control section" of DNA that stimulates gamma-to-beta switching, and join the ends back up to produce sustained elevation of fetal hemoglobin levels in adult red blood cells." When the scientists edited the DNA of blood-forming stem cells derived from patients with sickle cell disease, they were able to activate those genes and produce red that had enough fetal hemoglobin to be healthy.

Recently, scientists have used several gene editing approaches to manipulate for the possible treatment of and beta-thalassemia, including repair of specific disease-causing mutations and other strategies to inhibit gamma-to-beta switching. All of these approaches remain untested in patients.

"Our results represent an additional approach to these existing innovative strategies and compare favorably in terms of the levels of fetal hemoglobin that are produced by our experimental system," said Weiss. Using genome editing to restore the hereditary persistence of fetal hemoglobin is an attractive possibility, because it can be achieved relatively easily using current technologies. The condition is known to be benign in people who inherit similar naturally occurring mutations.

At this stage, the scientists emphasize that it is still too early to begin clinical trials of the new gene editing approach. The researchers want to refine further the gene editing process and perform other experiments to minimize potentially harmful off-target mutations before in-human clinical trials are considered. Additionally, it will be important to compare different approaches head-to-head to determine which one is safest and most effective.

Explore further: Gene editing study reveals possible 'Achilles heel' of sickle cell disease

More information: A genome-editing strategy to treat β-hemoglobinopathies that recapitulates a mutation associated with a benign genetic condition, nature.com/articles/doi:10.1038/nm.4170

Related Stories

Gene editing study reveals possible 'Achilles heel' of sickle cell disease

September 16, 2015
Researchers from Dana-Farber/Boston Children's Cancer and Blood Disorders Center have found that changes to a small stretch of DNA may circumvent the genetic defect behind sickle cell disease (SCD). The discovery, published ...

Forcing chromosomes into loops may switch off sickle cell disease

August 14, 2014
Scientists have altered key biological events in red blood cells, causing the cells to produce a form of hemoglobin normally absent after the newborn period. Because this hemoglobin is not affected by the inherited gene mutation ...

Multiple myeloma drug could revolutionize treatment for sickle cell disease

December 17, 2015
An established drug for recurrent multiple myeloma might effectively be repurposed to improve the survival and day-to-day lives of patients with devastating sickle cell disease, according to revealing new research by a Feinstein ...

Progress and promise of gene transfer and gene editing to cure beta-thalassemias

May 5, 2016
Promising results from the first clinical trials of globin gene transfer to treat beta-thalassemias-inherited forms of anemia-have eliminated the need for blood transfusions in some individuals. Enhancing current gene therapy ...

Discovery could help treatments for sickle cell disease

August 8, 2016
An interdisciplinary, international group of researchers has found new biophysical markers that could help improve the understanding of treatments for sickle cell disease, a step toward developing better methods for treating ...

Recommended for you

Make way for hemoglobin

August 18, 2017
Every cell in the body, whether skin or muscle or brain, starts out as a generic cell that acquires its unique characteristics after undergoing a process of specialization. Nowhere is this process more dramatic than it is ...

Bio-inspired materials give boost to regenerative medicine

August 18, 2017
What if one day, we could teach our bodies to self-heal like a lizard's tail, and make severe injury or disease no more threatening than a paper cut?

Are stem cells the link between bacteria and cancer?

August 17, 2017
Gastric carcinoma is one of the most common causes of cancer-related deaths, primarily because most patients present at an advanced stage of the disease. The main cause of this cancer is the bacterium Helicobacter pylori, ...

Two-step process leads to cell immortalization and cancer

August 17, 2017
A mutation that helps make cells immortal is critical to the development of a tumor, but new research at the University of California, Berkeley suggests that becoming immortal is a more complicated process than originally ...

Female mouse embryos actively remove male reproductive systems

August 17, 2017
A protein called COUP-TFII determines whether a mouse embryo develops a male reproductive tract, according to researchers at the National Institutes of Health and their colleagues at Baylor College of Medicine, Houston. The ...

New Pathology Atlas maps genes in cancer to accelerate progress in personalized medicine

August 17, 2017
A new Pathology Atlas is launched today with an analysis of all human genes in all major cancers showing the consequence of their corresponding protein levels for overall patient survival. The difference in expression patterns ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.