In Vivo Gene-Editing Model Shows Promise in Treating Blood Disorders

Researchers at Children's Hospital of Philadelphia (CHOP) and the Perelman School of Medicine at the University of Pennsylvania have developed a proof-of-concept model for delivering gene-editing tools to treat blood disorders. The novel approach, which was published in Science, enables the direct modification of diseased blood cells within the body, potentially eliminating the need for chemotherapy and stem cell transplants in gene therapies. This advancement could expand patient access and reduce the cost of treating blood disorders that currently require complex and expensive treatments.

Currently, treating hematologic diseases such as sickle cell disease and beta thalassemia with gene therapy involves patients receiving conditioning treatments like chemotherapy to make space for new, corrected blood cells. These conditioning procedures come with significant risks and toxic side effects. In contrast, the new model presented by the researchers demonstrates the possibility of replacing diseased blood cells with corrected ones directly within the body, streamlining the delivery of potentially life-changing gene therapies.

The research team employed liquid nanoparticle (LNP) technology to deliver mRNA gene-editing tools. To specifically target hematopoietic stem cells (HSCs), the cells responsible for producing all blood and immune system cells, the researchers decorated the LNPs with antibodies recognizing the CD117 receptor on the surface of HSCs. This targeted approach allowed them to test the efficacy of their CD117/LNP formulation through three different approaches.

First, they showed successful in vivo mRNA expression and gene editing using CD117/LNP encapsulating reporter mRNA. Next, they tested CD117/LNP encapsulating mRNA encoding a cas9 gene editor targeting the mutation responsible for sickle cell disease. The results demonstrated efficient base editing, converting the disease-causing hemoglobin mutation into a non-disease-causing variant, leading to a significant increase in functional hemoglobin and nearly complete elimination of sickled cells.

Furthermore, the researchers explored the possibility of using LNPs for in vivo conditioning, which would allow bone marrow depletion without the need for chemotherapy or radiation. They used CD117/LNP encapsulating mRNA for PUMA, a protein that promotes cell death, and effectively depleted HSCs in animal models, paving the way for successful engraftment of new bone marrow cells without the need for toxic conditioning treatments.

The potential implications of this research are vast. By enabling cell-type specific gene modification with minimal risk, this technique opens up new possibilities for manipulating blood stem cell physiology. Additionally, the precise delivery platform could be used to correct various monogenic disorders, significantly transforming gene therapy.