New sickle cell gene therapy shows promise in early mouse study

A novel gene therapy for sickle cell disease (SCD), designed to modify blood stem cells without the need to remove and transplant them back into patients, showed proof-of-concept results in humanized mice, a study found.

“Comprehensive [non-human primate] studies will be required to assess safety, biodistribution [how the therapy spreads through the body], immunogenicity [the ability to trigger an immune response], and therapeutic efficacy [how well it works] prior to clinical translation,” the researchers wrote.

The study, “Systemic delivery of phagocytosis-shielded retroviral vectors enables in vivo HSC gene therapy for sickle cell disease,” was published in Cell Stem Cell.

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Blocking key protein opens potential new path for SCD treatment

Current gene therapies require complex procedures

SCD is a genetic disorder that causes the body to produce an abnormal form of hemoglobin, the protein in red blood cells that carries oxygen. This abnormal hemoglobin can clump together, causing red blood cells to take on a sickle shape and leading to SCD symptoms.

Hematopoietic stem cells, or HSCs, are found in the bone marrow and give rise to new blood cells. Gene therapies for SCD aim to modify these cells so they produce red blood cells with hemoglobin that helps prevent sickling, addressing the underlying cause of the disease. In some cases, gene therapy may provide a functional cure.

Two gene therapies are currently approved in the U.S. for SCD: Lyfgenia (lovotibeglogene autotemcel), which works by modifying HSCs to produce a form of adult hemoglobin that helps prevent sickling, and Casgevy (exagamglogene autotemcel), which modifies HSCs to increase production of fetal hemoglobin, a form of the protein that also helps prevent sickling.

Both Lyfgenia and Casgevy are designed to modify stem cells outside the body, a process called ex vivo gene therapy. A patient’s HSCs are collected and modified in a laboratory before being infused back into the body. Before the infusion, patients must undergo high-intensity chemotherapy to destroy existing blood-forming cells and make room for the modified cells.

Although ex vivo gene therapies have shown benefits in clinical trials, they have notable limitations. Collecting, modifying, and returning patients’ cells is expensive and time-consuming. The high-intensity chemotherapy required before infusion also carries substantial safety risks.

New approach targets blood stem cells inside the body

An international team of researchers developed an approach to modify HSCs directly inside the body (in vivo). Rather than collecting and modifying the cells in a lab, the approach would involve injecting a gene therapy that modifies HSCs inside the patient.

“Direct in vivo genetic modification of HSCs through a simple injectable approach could address [limitations of ex vivo gene therapy] and potentially render gene therapy more accessible, cost-effective, and safer,” the researchers wrote. “This is particularly relevant for SCD, for which the global number of affected individuals is estimated to exceed 7 million, the majority residing in Africa and India.”

To develop the therapy, the researchers used an engineered virus to deliver genetic instructions designed to increase fetal hemoglobin production. These instructions reduce the activity of two genes, BCL11A and ZNF410, that normally suppress fetal hemoglobin production in developing red blood cells.

The researchers also modified the virus to help it enter HSCs and avoid certain immune defenses. They added a protein derived from a baboon virus to its outer surface and increased levels of CD47, a naturally occurring protein that helps prevent immune cells from engulfing and removing the virus.

Chemotherapy helps increase genetically modified stem cells

As a final modification, the researchers added a gene that made modified HSCs resistant to a specific chemotherapy regimen. This allowed them to give mice the gene therapy, followed by chemotherapy that reduced the number of unmodified cells while allowing more of the modified cells to survive.

The researchers then tested the new gene therapy in mice transplanted with human blood stem and progenitor cells. These humanized mice allowed the team to study how the therapy affected human cells inside a living body.

Because most HSCs normally remain in the bone marrow, delivering genetic material to them inside the body can be difficult. Before administering the gene therapy, the researchers treated the mice with drugs that moved human blood stem and progenitor cells from the bone marrow into the bloodstream, making them easier to reach.

By week 16, the gene therapy had successfully modified an average of 53.7% of human HSCs and related progenitor cells in the mice’s bone marrow, following chemotherapy-based selection. Laboratory tests of cells collected from the mice also showed a significant increase in gamma-globin, a component of fetal hemoglobin, reaching levels the researchers considered therapeutically relevant for sickle cell disease.

“Taken together, these data demonstrate the feasibility of in vivo gene therapy to induce therapeutically relevant levels of [fetal hemoglobin] for SCD,” the researchers wrote. They emphasized, however, that additional preclinical safety testing is needed before the approach can be tried in people.