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From Viruses to Lipid Nanoparticles: A Focus on Non-Viral Integrating Gene Therapy for Classical Hematologic Disorders

December 11, 2022

It is hard to believe that until recently, allogeneic stem cell transplantation was the only curative treatment available for patients with inherited disorders of the blood and bone marrow. This year, three gene therapy products (and many others in the development pipeline) are ready for prime time. Valoctocogene roxaparvovecv received approval in Europe to treat hemophilia A. In the United States, the U.S. Food and Drug Administration authorized beti-cel (betibeglogene autotemcel) for patients with β-thalassemia, and etranacogene dezaparvovec for the treatment of adults with hemophilia B. The first-to-market gene therapies for patients with hemophilia have used adeno-associated viral (AAV) vectors, while those for hemoglobinopathies rely on edited autologous CD34+ hematopoietic stem cells (HSPCs).

The promise of durable treatment effect does not come without risks and challenges at the safety, efficacy, manufacturing, and cost levels. AAV vector therapy is limited to transgene sizes of less than 4.8 kbp, is affected by the immunogenicity of the viral capsid, and in some patients, does not provide sustained FVIII production to cure hemophilia A. Conversely, lentiviral vector transduction and electroporation for gene transfer have been the main modalities used for modification of HSPCs. This strategy, however, requires administration of conditioning cytotoxic chemotherapy and/or radiation therapy, which has significant short- and long-term toxicities.

One of the greatest qualities of a scientist is the desire to continually improve; as novel technologies make it to the bedside, a new wave of promising improvements is simultaneously being developed in the laboratory. Dr. Laura Breda (session 801, abstract 123) presented novel methods for genomic editing using mRNA encapsulated in lipid nanoparticles at the session on Gene Therapies: Addressing Challenges and Opportunities in Pre-clinical Settings.” Lipid nanoparticles that encase a ring of lipids around mRNA cargo would typically be taken up by the liver, conjugating it with an antibody with specificity to hematopoietic stem cells allows localization in the bone marrow. This approach not only targets hematopoietic precursors to correct monogenic disorders but also opens the door to the possibility of hematopoietic stem cell depletion using a non-genotoxic conditioning regimen that would revolutionize transplant associated risks, especially for patients with inherited defects in DNA mismatch repair.

Are two nanoparticles better than one? The mouse model for the piggyBac® platform to be presented by Dr. Truong (session 321, abstract 400) during the Coagulation and Fibrinolysis: Basic and Translational session is composed of two nanoparticles: one lipid nanoparticle containing the transposase as mRNA and another containing a plasmid with the human F8 gene, promoter, and piggyBac inverted terminal repeats. Administered intravenously and delivered to the liver, it promises sustained FVIII production through stable transgene expression, an advantage over the transient expression of nonintegrating gene therapy, which is observed with other systems such as adeno-associated viral vectors.

The opportunity to provide treatments that restore gene function in patients with monogenic disorders gets us closer to having true cures. Short- and long-term toxicity and sustainability of responses will be a big challenge. The future looks bright, and everyone in the hematology community is looking forward to seeing where gene therapy take us in the near and distant future.


Dr Perez Botero indicated no relevant conflicts of interest.

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