Researchers at Children’s Hospital of Philadelphia (CHOP) and the Perelman School of Medicine at the University of Pennsylvania have successfully developed a proof-of-concept model for delivering gene editing tools to treat blood disorders, enabling the direct modification of diseased blood cells within the body. The model could lead to expanded access and cost reduction for gene therapies targeting various blood disorders, which often involve chemotherapy and stem cell transplants.

Co-senior author Stefano Rivella, PhD, emphasized the current challenges in treating hematologic diseases like sickle cell disease and beta thalassemia with gene therapy. Presently, patients require conditioning treatments like chemotherapy to create space for the corrected blood cells, which is not only expensive but also carries inherent risks. However, their research demonstrates the feasibility of replacing diseased blood cells with corrected ones directly within the body, effectively eliminating the need for myeloablative conditioning treatments. This novel approach streamlines the delivery of potentially life-changing gene therapies, offering new possibilities for treating genetic diseases more efficiently.

The study’s senior author, Hamideh Parhiz, PharmD, PhD, highlights the profound impact of targeted delivery of mRNA-encoded therapeutics to specific tissues and cell types, which could revolutionize disease treatment with nucleic acids. By employing a cell-specific targeted lipid nanoparticle encapsulating mRNA therapeutics, the researchers have opened doors for in vivo cellular reprogramming in numerous diseases requiring precisely targeted gene therapy modalities. Their groundbreaking work integrates targeted platforms with advancements in mRNA therapeutics and RNA-based genomic editing tools, leading to better control over hematopoietic stem cell fate and genetic defect correction. This targeted mRNA-encoded genomic editing methodology exhibits potential for safer and more effective in vivo genomic modification compared to current technologies.

The research primarily focuses on hematopoietic stem cells (HSCs), residing in the bone marrow, responsible for generating all blood and immune system cells throughout life. Non-malignant hematopoietic disorders, like sickle cell disease and immunodeficiency disorders, result from genetic mutations disrupting proper blood cell function.

Current curative treatments involve either a stem cell transplant with healthy donor HSCs or ex vivo gene therapy using modified patient HSCs. Both methods necessitate conditioning regimens, involving chemotherapy or radiation, to prepare the body to receive the new cells. The risk of graft versus host disease is also present in donor stem cell transplants, and both procedures come with toxic side effects, driving the need for less-toxic alternatives.

The in vivo gene editing approach holds the potential to revolutionize gene therapy, allowing for cell-type specific gene modification with minimal risk. By targeting HSCs directly within the patient’s body, this technique avoids the complexities of conditioning regimens. The research team achieved this by using liquid nanoparticles (LNPs) to deliver mRNA gene editing tools, specifically decorated to recognize CD117, a receptor found on the surface of HSCs. This targeted CD117/LNP formulation demonstrated successful in vivo mRNA expression and gene editing, making it a promising candidate for future hematologic disease therapies.

This transformative research has the potential to usher in a new era of gene therapy, making previously unattainable manipulations of blood stem cell physiology possible. As the platform holds promise for correcting diverse monogenic disorders, it may impact the treatment landscape for a wide array of human diseases. The study was supported by the National Institutes of Health (NIH) grants, The Thomas B. and Jeannette E. Laws McCabe Fund at the University of Pennsylvania, and the W.W. Smith Charitable Trust Fund, marking an important milestone in the development of genetic medicines.

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Journal Reference:

Breda L, Papp TE, Triebwasser MP, Yadegari A, Fedorky MT, Tanaka N, Abdulmalik O, Pavani G, Wang Y, Grupp SA, Chou ST, Ni H, Mui BL, Tam YK, Weissman D, Rivella S, Parhiz H. In vivo hematopoietic stem cell modification by mRNA delivery. Science. 2023 Jul 28;381(6656):436-443. doi: 10.1126/science.ade6967. Epub 2023 Jul 27. PMID: 37499029.

In vivo hematopoietic stem cell modification by mRNA delivery

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