CRISPR is able to circumvent the genetic mutation that causes sickle cell disease.
The latest Sickle Cell Research from Dana-Farber/Boston Children’s Cancer and Blood Disorders Center is that they have found that changes to a small stretch of DNA may circumvent the genetic defect behind sickle cell disease. They are developing gene-editing approaches to treat the disease and other hemoglobin disorders.
This stretch of DNA, called an enhancer, controls a molecular switch that determines whether a red blood cell produces the adult form of hemoglobin which in sickle cell disease is mutated or a fetal form that is unaffected by and counteracts the effects of the mutation
Studies have indicated that sickle-cell patients with elevated levels of fetal hemoglobin have a milder form of the disease.
The research was spurred by the discovery that naturally occurring beneficial variations in the DNA sequence in this enhancer dial down the molecular switch only in red blood cells. In an attempt to mimic and improve upon the natural variations, the researchers developed CRISPR-based gene editing tools to systematically cut out tiny sections of DNA step-by-step along the entire length of the enhancer in blood stem cells from human donors.
The team then allowed the cells to mature into red blood cells and found that the amount of fetal hemoglobin the cells produced had increased dramatically. Additionally, the scientists discovered a specific location in the enhancer that when cut leads to the production of high levels of fetal hemoglobin.
Parallel experiments in an animal model revealed that removal of this part of the enhancer affected the molecular switch’s expression only in red blood cells, not in immune or brain cells, where the switch is also active.
These experiments may have revealed the genetic Achilles heel of sickle cell disease.
Although fixing the sickle mutation itself would seem the most straightforward approach, it turns out that blood stem cells, the ultimate targets for this kind of therapy, are much more resistant to genetic repair than to genetic disruption.
Thus making a single DNA cut that breaks the enhancer solely in blood stem cells could be a much more feasible strategy
For more information please visit: harvard.edu
