New off-the-shelf gene editing may treat sickle cell without transplant
Single dose safely corrected primate stem cells to levels considered curative
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An experimental, single-dose gene-editing therapy from Tessera Therapeutics successfully corrected the genetic mutation that causes sickle cell disease (SCD) in the majority of blood-forming stem cells in nonhuman primates, reaching levels that surpass what is expected to cure the disease.
The new preclinical data were presented by Tessera at the annual meeting of the American Society of Gene and Cell Therapy and announced in a company press release.
This off-the-shelf therapy is designed to correct the SCD-causing mutation in blood-forming, or hematopoietic, stem cells directly inside a patient’s body, a process known as in vivo editing. This differs from currently approved SCD gene therapies, which require collecting and genetically modifying a patient’s stem cells outside the body before transplanting them back.
The burden of current sickle cell treatments
The preclinical findings suggest the therapy could one day offer a less burdensome alternative to current gene-editing therapies.
“Our latest data represent a significant advancement towards demonstrating the potential of an in vivo Gene Writing program as a transformative approach for genetic medicine,” said Michael Severino, MD, Tessera’s CEO.
SCD is caused by mutations in the HBB gene that lead to the production of an abnormal form of hemoglobin, the oxygen-carrying protein in red blood cells. As a result, red blood cells become rigid and sickle-shaped, increasing their tendency to break down and clump together, blocking small blood vessels.
This can cause anemia, a shortage of healthy red blood cells, and problems with blood flow, damaging tissues and organs, and triggering painful episodes known as vaso-occlusive crises.
Gene therapies have emerged in recent years as a promising treatment approach for SCD. These therapies aim to modify the genetic code of hematopoietic stem cells, the cells in bone marrow that produce all types of blood cells, to ultimately enable long-term production of healthy red blood cells.
Currently approved gene-editing therapies for SCD, such as Casgevy (exagamglogene autotemcel) and Lyfgeniav (lovotibeglogene autotemcel), are designed to work outside the body (ex vivo).
Briefly, hematopoietic stem cells are collected from a patient’s bone marrow, treated in the lab with gene therapy, and then returned to the body via a stem cell transplant. Before the transplant, patients undergo myeloablative conditioning, an intensive course of chemotherapy and/or radiation therapy, to destroy all or most stem cells in the bone marrow to make room for the new, modified cells. This regimen has its own health risks.
Writing genes directly inside the body
Tessera is pursuing a different strategy designed to perform gene editing directly inside the body using its proprietary Gene Writing technology. Such an approach has the potential to eliminate the need to undergo an invasive, risky stem cell transplant.
The company’s experimental therapy, delivered directly to hematopoietic stem cells via tiny fat-based vesicles, is designed to correct the HBB mutation responsible for SCD. This is expected to restore production of healthy hemoglobin, helping prevent red blood cells from becoming rigid and sickle-shaped and easing symptoms.
In previous studies in nonhuman primates, Tessera reported about 40% of hematopoietic stem cells carried at least one edited copy of the HBB gene after a single dose of the therapy, increasing to roughly 60% with repeat dosing.
According to the company, these levels exceeded the estimated 20% to 30% of edited cells believed to be associated with meaningful clinical benefit, including the resolution of pain crises and a reduction in anemia.
The newly presented data extended these findings. In nonhuman primates, a single dose of an optimized Gene Writer therapy corrected at least one copy of the HBB gene in an average of 85% of hematopoietic stem cells. Tessera said these levels fall within the range of editing rates reported for approved ex vivo gene therapies.
The company also reported that HBB editing persisted for up to 19 months (about 1.5 years) after treatment and was detected across multiple blood cell types, suggesting the modified stem cells remained functional and continued producing different types of blood cells over time. The therapy was reported to be well tolerated.
“In non-human primates, a single dose of our Gene Writer achieved levels of editing in long-term hematopoietic stem cells that are well above the levels believed to be required for curative benefit in sickle cell disease,” Severino said. “Notably, this was accomplished without stem cell mobilization, myeloablative conditioning, or transplantation.”
