This week we profile a recent publication in Blood Advances from the laboratory of Dr. Carol Miao (pictured, front row, left) at UW, Seattle Children’s, and Fred Hutch.
Can you provide a brief overview of your lab’s current research focus?
My lab focuses on investigating potentially clinically translatable approaches for hemophilia treatment. The goal is to develop safe and more effective treatment protocols and regimens to achieve a long-term therapeutic effect. We are currently pursuing the following major research programs: the development of safe and more efficient gene therapy approaches suitable for clinical applications including nonviral ultrasound-mediated gene delivery (UMGD), gene delivery using lipid nanoparticles, direct bone marrow transduction using lentiviral gene transfer methods, and most recently, gene editing technology; and development of immunomodulation strategies involving immunosuppressive regimens and adoptive regulatory T cell therapy for treating inhibitory antibodies following gene or protein replacement therapy. Furthermore, in collaboration with glycobiology labs, we participate in an NIH U54 program to study the impact of glycosylation on factor VIII immunogenicity. These studies will facilitate the translation of new successful gene therapy and immunomodulation strategies to clinical hemophilia treatment.
What is the significance of the findings in this publication?
Gene therapy holds significant potential to offer alternative long-term treatment of hemophilia in place of costly and inconvenient frequent infusions of factor VIII (FVIII) protein for hemophilia treatment. Intraosseous (IO) delivery of megakaryocyte-specific lentiviral vectors (LV) can transduce primitive hematopoietic stem and progenitor cells (HSPCs) to achieve long-term phenotypic correction in hemophilia A mice. Ectopic localization within platelet alpha-granules protects FVIII from detection by circulating antigen-presenting cells. Meanwhile, at the site of injury, platelets activate and release FVIII locally, allowing for amplification of the coagulation cascade while minimizing the risk of generating inhibitors.
To facilitate the translation of this technology to human applications, we evaluated the safety and efficacy of this gene transfer therapy in human HSCs. We showed that G-F8-LV can efficiently transduce primitive HSCs both in vitro and in vivo, leading to persistent FVIII expression in human megakaryocytes and platelets. Retroviral integration analysis detected a polyclonal integration pattern in G-F8-LV transduced human cells, profiling the clinical safety of hemophilia treatment. Our results demonstrate the long-term safety and efficacy of IO-LV gene therapy strategy for hemophilia A treatment, adding further evidence to the feasibility of translating this novel method for clinical applications.
What are the next steps for this research?
We continue to explore the best approaches to increase the safety and efficacy of IO-LV gene therapy treatment for hemophilia. We are actively looking for an industrial partnership to push forward this novel technology for clinical translation. The next step will be to work on filing Pre-IND to prepare for clinical trials using this technology to treat hemophilia patients. We are also interested in extending the use of this technology to treat other diseases.
If you’d like us to mention your funding sources, please list them.
This work has mainly been supported by grants from NIH/NHLBI.
