Gene Editing, mRNA Hold Promise as Fanconi Anemia Therapies

Gene therapies could have a major impact, although the cost and complexities could inhibit their wide rollout, study authors said.

New advancements in gene therapy and hematopoietic stem cell generation could lead to a dramatically new treatment paradigm for people with Fanconi anemia (FA).

That is the major finding of a newly published review that examined how a better understanding in the scientific and molecular underpinnings of the disease has translated into potential new therapeutic avenues. The review was published in Blood Reviews.

FA is a rare genetic disorder with a wide range of manifestations and symptoms, wrote the study investigators. The condition affects the bone marrow and results in decreased production of all types of blood cells. Some patients develop skeletal abnormalities, kidney problems, or hearing loss, while others have no obvious physical symptoms, they said. More than 20 genes have been linked to FA.

Treatment for the disease typically centers around hematopoietic stem cell transplantation (HSCT), the investigators noted. But although HSCT can cure bone marrow failure and hematological malignancies, it does not benefit all patients, they said.

“Additionally, due to the intrinsic role of FA proteins, FA patients have a higher risk of morbidity during or after HSCT,” they wrote. “This is mainly due to the toxicity of the radiation or chemotherapy used during pretransplant conditioning.”

Other complications, including graft-versus-host disease and certain types of cancer, are also possible following HSCT, they added.

The authors said the limitations and complications of HSCT underscore the need for additional therapeutic choices. However, they said progress on new options has been swift of late. One new treatment option is gene therapy. The authors said the development of CRISPR-Cas9 technology has made gene editing a scientifically feasible strategy to correct mutations associated with FA.

“The general strategy is to introduce ex vivo the wild-type version of the patient's mutated gene (gene addition) or to correct the mutated gene (gene editing) using viral vectors,” they said.

Another avenue of treating FA is to generate hematopoietic stem cells using induced

pluripotent stem cells, they said. However, the problem, they said, is that there is a difference between scientific feasibility and real-world feasibility.

“Thanks to the development of these new gene editing strategies, the therapeutic application of gene editing in hematological disorders including FA is very close,” they wrote, “but due to current cost and ethical questions, it may have [reached] its glass ceiling and may be difficult to apply to a large number of patients.”

That’s why the authors also proposed investigating the potential of messenger RNA (mRNA)-based therapies.

“The recent success of mRNA vaccines in the fight against COVID-19 has significantly advanced the idea of mRNA therapeutics as a promising new class of medicine,” they wrote.

Two possibilities, they said, would be to use mRNA “as a drug” to compensate for a defective gene or protein or to use mRNA for cell therapy by modifying cells ex vivo and then reinfusing them into the patient.

They said mRNA therapies may be safer and relatively simpler than DNA-based therapies.

The authors said a significant amount of research will need to be completed to better understand which therapies are best, but they said there is significant reason for optimism.

“While this type of application still presents challenges in terms of repeated administration, tissue targeting, and stability, mRNA therapeutics is a rapidly emerging field with unexplored capacity to treat FA disease,” they said.


Elena MB, Jean-Hugues G, Pérez-Oliva AB, et al. Beyond current treatment of Fanconi anemia: what do advances in cell and gene-based approaches offer? Blood Reviews. Published online April 28, 2023. doi:10.1016/j.blre.2023.101094

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