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Streamlined Gene Therapy Delivery Process Demonstrated

Sickle cells illustration

Sickle cells illustration (Open Stax College, Wikimedia commons,

27 July 2023. A group of academic and industry researchers exhibited in lab cells and mice a more direct delivery technique that could make gene therapies more accessible and inexpensive. Researchers from University of Pennsylvania medical school in Philadelphia, Children’s Hospital of Philadelphia, and the biotechnology company Acuitas Therapeutics in Vancouver, British Columbia describe their process in today’s issue of the journal Science (paid subscription required).

A team led by pediatric geneticist Stefano Rivella of Children’s Hospital and UPenn cell biologist Hamideh Parhiz are seeking to make gene therapies and gene-editing treatments more feasible, as well as bone marrow transplant therapies overall. In most cases, gene therapies or transplants into bone marrow require transferring hematopoietic or blood-forming stem cells from healthy matched donors or the patient’s own modified stem cells. But this process, called myeloablation, requires extensive conditioning of the recipient’s bone marrow, generally with chemotherapy or radiation, to make room for the transplanted cells or therapies, a risky process for many patients.

The researchers in this study demonstrate an alternative approach for delivering gene therapies or healthy stem cells to bone marrow that skips a separate conditioning step and makes possible a more straightforward transfer method. The team adapted nanoscale lipid or natural oil particles to deliver messenger RNA or mRNA, synthesized nucleic acid with protein-making instructions transcribed from DNA, a technique used in vaccines protecting against Covid-19 disease. In this case, the lipid nanoparticles target receptor proteins for CD117, a gene that plays a key role in formation of blood stem cells, with an antibody that conditions recipient bone marrow cells.

Lipid nanoparticles deliver gene-editing payloads

The team demonstrated an in vivo or inside-the-body conditioning process in lab mice, with a single injection of lipid nanoparticles carrying mRNA coding for the CD117-targeting antibody. The results show the lipid nanoparticles deliver their antibody payloads and condition blood-forming cells in mice, without chemotherapy or radiation. In a separate lab test, researchers delivered gene-editing RNA in lipid nanoparticles to blood samples from four individuals with sickle cell disease. Here, findings indicate lipid nanoparticles can deliver the gene-editing payloads to correct defects responsible for the disease, resulting in almost a complete absence of the malformed red blood cells.

“Right now, if you want to treat hematologic diseases like sickle cell disease and beta thalassemia with gene therapy,” says Rivella in a Children’s Hospital of Philadelphia statement released through Cision, “patients must receive conditioning treatments like chemotherapy to make space for the new, corrected blood cells, which is both expensive and comes with risks. In our paper, we have shown that it is possible to replace diseased blood cells with corrected ones directly within the body in a ‘one-and-done’ therapy, eliminating the need for myeloablative conditioning treatments and streamlining the delivery of these potentially life-changing treatments.”

Acuitas Therapeutics provided two participants for the study team. The company develops synthetic lipid nanoparticles for vaccines and therapeutics, including delivery of mRNA. The paper indicates, however, that University of Pennsylvania filed for a series of patents on the technologies in the paper between Dec. 2022 and May 2023, including gene editing of blood-forming stem cells with lipid nanoparticles and in vivo conditioning of blood-forming cells with mRNA delivered by lipid nanoparticles.

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