TALEN Gene Editing Corrects Sickle Cell Mutations in Preclinical Tests
Platform corrected the HBB gene mutation in 68% to 79% of cells
A gene editing platform developed by Cellectis called TALEN was able to restore healthy hemoglobin production in preclinical models of sickle cell disease (SCD).
That’s according to data presented by Arianna Moiani, PhD, senior scientist and team leader of Innovation Gene Therapy at Cellectis, at the 29th Congress of the European Society of Gene and Cell Therapy (ESGCT), in Edinburgh, Oct. 11–14. The oral presentation was titled, “Non-viral DNA delivery associated to TALEN gene editing leads to highly efficient correction of sickle cell mutation in long-term repopulating hematopoietic stem cells.”
“The pre-clinical data presented at ESGCT further demonstrate our ability to leverage TALEN gene editing technology to potentially address genetic diseases,” Philippe Duchateau, PhD, chief scientific officer at Cellectis, said in a press release. “These new milestones bring us one step closer to our goal: providing a cure to patients that have failed to respond to standard therapy.”
SCD is caused by mutations in a gene called HBB that provides instructions for making hemoglobin, the protein that red blood cells use to carry oxygen through the body. As a result of these mutations, an abnormal form of hemoglobin is produced, which tends to clump up, deforming red blood cells into the “sickle-like” shape that gives the disease its name.
The TALEN platform uses specialized proteins called transcription activator-like effectors, or TALEs, to target and alter a specific point in a cell’s genetic code. The basic idea behind gene editing in SCD is to “correct” the disease-causing mutation, thereby restoring healthy hemoglobin production.
Scientists at Cellectis used the TALEN platform to edit the HBB gene in hematopoietic stem and progenitor cells (HSPCs) from people with SCD. HSPCs are the cells in bone marrow that give rise to red blood cells and other types of blood cells.
Results showed the platform could correct the HBB mutation in 68% to 79% of cells. The rate of off-target effects that reduced hemoglobin production was lower than 10% in these experiments.
In other experiments, HSPCs were grown to produce red blood cells, which were then further characterized. Results showed TALEN-corrected cells had a substantial increase in normal hemoglobin production.
While nearly all red blood cells generated from unaltered HSPCs took on the characteristic “sickle-like” shape, only about 25% of red blood cells generated from TALEN-edited HSPCs were sickled. The rest had the round, discoid shape typical of healthy red blood cells.
In a final set of experiments, scientists showed TALEN-edited HSPCs could be transplanted into the bone marrow of mice, and could survive and produce blood cells there.
“By correcting a faulty mutation or inserting a corrected gene at the HSPC level, we aim to provide a lifelong supply of healthy cells in a single intervention,” Duchateau said.