Editas’ new gene-editing strategy for SCD shows promise in mice
Company's in vivo approach would not involve stem cell transplant
Editas Medicine has announced proof-of-concept data for a new gene-editing approach for sickle cell disease (SCD) that does not involve a stem cell transplant.
The strategy instead makes use of targeted lipid nanoparticles, or LNPs, which are tiny vesicles made of fatty molecules. They are used to deliver to a patient’s blood progenitor cells a gene-editing machinery that’s designed to increase the production of fetal hemoglobin, which can compensate for the mutated adult version of the protein that’s produced in SCD.
Results from mice genetically modified to have human blood cell progenitors showed that a single dose of the new treatment approach effectively promoted the production of fetal hemoglobin in about 20% of red blood cells.
“Achieving in vivo [inside a living body] preclinical proof of concept in a desired, [non-liver] target cell type, delivered utilizing a proprietary Editas LNP that works outside the liver, puts us on a clear path to develop a potentially first- and best-in-class in vivo gene edited medicine for the treatment of sickle cell disease,” Gilmore O’Neill, president and CEO of Editas, said in a company press release. O’Neill called the new findings “concrete progress.”
New strategy is based on in vivo, meaning inside the body, approach
Sickle cell disease is caused by mutations in a gene needed to produce hemoglobin, the protein used by red blood cells to carry oxygen through the bloodstream. The abnormal hemoglobin that results clumps up in blood cells, deforming them and ultimately driving disease symptoms.
SCD specifically impacts the adult version of hemoglobin. Another form of the protein, called fetal hemoglobin, is made during early development in the womb and is better at transporting oxygen. However, its production is replaced by that of its adult counterpart shortly after birth.
Gene editing, a technology that acts to change the genetic code within a cell, can be used to increase fetal hemoglobin production by altering the genetic code of hematopoietic stem cells, or HSCs. These stem cells live in the bone marrow and are responsible for making new blood cells.
Increasing the production of fetal hemoglobin can help compensate for the mutated adult version of the protein, ultimately helping to lessen SCD symptoms and complications.
That’s how Casgevy (exagamglogene autotemcel) — the first-ever approved SCD therapy using the CRISPR/Cas9 gene-editing tool — works. Developed by CRISPR Therapeutics and Vertex Pharmaceuticals, Casgevy is an ex vivo, or outside the body, treatment.
This means that a person’s HSCs have to be collected, taken to a lab to undergo editing, and then transplanted back into the patient via a stem cell transplant, which can be a time-consuming and arduous process.
Editas’ new approach is meant to be an in vivo gene-editing treatment that allows HSCs to be edited within the patient’s body, effectively eliminating the need for a stem cell transplant. Not having to undergo such a transplant would be expected to lessen the treatment burden for patients.
Study in mice provides Editas proof-of-concept data
The novel strategy uses the company’s proprietary targeted LNPs, which are designed to deliver a CRISPR gene-editing machinery to HSCs in the bone marrow.
In mice engineered to have human hematopoietic stem cells, a single dose of this in vivo approach led to the successful editing of 29% of the stem cells. Within a month of the gene-editing treatment, about one-fifth (approximately 20%) of the mice’s human red blood cells were producing fetal hemoglobin.
“This level of in vivo editing in a humanized [mouse] model after a single dose constitutes a highly competitive dataset relative to [that] in the public domain for the development of an in vivo medicine for sickle cell disease,” Linda C. Burkly, PhD, Editas’ executive vice president and chief scientific officer, stated in a company webcast.
[The result of this preclinical testing] creates the opportunity for a first- and best-in-class in vivo [inside a living body] medicine for the treatment of sickle cell disease.
These proof-of-concept data are “significant for multiple reasons,” Burkly said, including the design of a “novel HSC targeting strategy and a proprietary LNP to deliver our editing cargo,” as well as the use of “a clinically validated target and enzyme” for SCD. These competitive data show a functional outcome in fetal hemoglobin production, Burkly noted.
Altogether, the result “creates the opportunity for a first- and best-in-class in vivo medicine for the treatment of sickle cell disease,” Burkly added.
Editas also has been developing an ex vivo gene-editing therapy for SCD, called renizgamglogene autogedtemcel (reni-cel), that works similarly to Casgevy. That therapy is being tested in a Phase 1/2/3 clinical trial called RUBY (NCT04853576) that completed enrollment early this year, with participants ranging in age from 12 to 50.
The company has said, however, that it plans to focus its resources on advancing the new in vivo approach, and will look for partners to help with or fully take over the reni-cel program.
“We believe that the best option for both patients and our shareholders is for us to seek an alternative such as a global partner or out-licensing, which would allow for further development and ultimately commercialization of reni-cel with or by another party and would allow us to substantially reduce [spending] in 2025,” O’Neill said.
About the Author
