Treatments for Hemophilia – Intraosseus Lentiviral Vector Delivery

Intraosseous delivery of lentiviral vectors targeting factor VIII expression in platelets for hemophilia A treatment

Technology Overview

Intraosseous (IO) infusion of lentiviral vectors (LVs) for in situ gene transfer into bone marrow may avoid specific challenges posed by ex vivo gene delivery, including, in particular, the requirement of pre-conditioning. Dr. Carol Miao and her colleagues have successfully transduced a high percentage of hematopoietic stem cells (up to 50% in bone marrow following IO delivery of high-titer LVs).

Dr. Carol Miao

Furthermore, by IO delivery of G-F8-LV encoding a factor VIII (FVIII) transgene directed by a platelet-specific, glycoprotein-1bα promoter, we achieved long-term platelet-specific expression of FVIII, resulting in partial correction of hemophilia A. Similar clinical benefit with G-F8-LV was achieved in animals with pre-existing anti-FBIII inhibitors. These findings further support platelets as an ideal FVIII delivery vehicle, as FVIII, storied in α-granules, is protected from neutralizing antibodies and, during bleeding, activated platelets locally excrete FVIII to promote clot formation.

Overall, a single IO infusion of G-F8-LV was sufficient to correct hemophilia phenotype for long term. We would like to pursue this new methodology for clinical trials in the near future. This method, in particular, would be of significant benefit for the very challenging patients who have developed inhibitory antibodies against FVIII.

Stage of Development

• Pre-clinical in vivo
• Pre-clinical in vitro

Partnering Opportunities

• Collaborative research opportunity
• Sponsored research agreement
• Consultation agreement

Publications

1. Miao CH. Hemophilia A gene therapy via intraosseous delivery of factor VIII-lentiviral vectors. Thromb J.,2016 Oct 4;14(Suppl 1):41. eCollection 2016. Review.
2. Wang X, Shin SC, Chiang A, Pan D., Rawlings DJ, Miao CH. (2013) Murine Hemophilia A with our without pre-existing anti-factor VIII inhibitors is partially corrected by factor VIII stored in platelets after intraosseous infusion of lentiviral vectors into bone marrow without preconditioning. American Society of Hematology, 55th Annual Meeting and Exposition. Abs. 719.
3. Wang X, Shin SC, Chiang AF, Khan I, Pan D., Rawlings DJ, Miao CH. (2015) Intraosseous delivery of lentiviral vectors targeting factor VIII expression in platelets corrects murine hemophilia. A. Mol. Ther. 2015 Feb 6. [Epub ahead of print].

Learn More

• Carol H. Miao, PhD