Platelet Targeted Therapeutics has developed a lentiviral gene transfer vector Pleightlet™ method to genetically modify Hematopoietic Stem Cells (HSC) for long-term production of blood platelets that synthesize, store, and secrete FVIII directly at the site of a vascular injury to repair damaged blood vessels without alerting the immune system. Platelet delivery of FVIII may be considered a “Trojan Horse” for Hemophilia A because FVIII is genetically synthesized in platelets, then stored hidden in the α-granule compartments until platelets become activated to repair a vascular injury and secrete the contents of their granules directly at the wound site on the damaged blood vessel, without alerting the immune system to the presence of a de novo FVIII molecule within the body.
Our therapeutic approach is novel to other treatment modalities that deliver recombinant FVIII to the blood plasma with protein replacement therapy or gene transfer targeting FVIII synthesis in the liver. With our positioning of this form of Factor VIII, which we call Pleightlet™, there is no circulating FVIII within the plasma available for recognition by the immune system.
Our approach is supported by 25 years of pre-clinical gene transfer studies in human cells grown in the research laboratory as well as animal models (mice and dogs) affected with hemophilia A, which has been demonstrated to safely improve hemostasis in the animal model without the detection of formation of inhibitory antibodies to FVIII in mice and dogs that are very sensitive to human FVIII. In addition, Pleightlet™ also has been shown capable of restoring hemostasis in mice with a history of inhibitory antibodies. A clinically relevant treatment protocol was developed in dogs, which improved hemostasis in a canine model of hemophilia A for at least six years after HSC transplant. Based upon the results of these studies, a Phase I First-In-Human clinical trial is currently underway. For more information regarding this clinical trial, click here.
Platelet Targeted Therapeutics, LLC has developed a lentiviral gene transfer vector method with the potential to restore proper platelet function for individuals afflicted with Glanzmann Thrombasthenia safely, efficiently, and permanently.
While earlier approaches used bone marrow transplants with varying outcomes, Platelet Targeted Therapeutics has developed a technique which uses genetically modified Hematopoietic Stem Cells (HSC, aka Bone Marrow Stem Cells) to produce blood platelets that carry the correct replacement gene ITGA2B (GPIIb) and ITGB3 (GPIIIa) for the correction of the relevant defective gene for individuals afflicted with Glanzmann Thrombasthenia.
From nearly 30 years of diligent research, we have developed a technique using a very specific stem cell gene transfer technique and lineage-specific endogenous gene promoters to target transgene expression to a specific cell type. HSC appear to be ideal targets for platelet gene therapy in that they differentiate into megakaryocytes, which then form an abundance of anucleate platelets that circulate within blood vessels to establish hemostasis by repairing vascular injury.
We developed a strategy which uses an ITGA2B gene promoter fragment to achieve a significant level of protein expression in human megakaryocytes. We demonstrated the validity of this approach in CD34+PBSCderived from two patients with GT, which is caused by mutations in ITGB3. By inserting a ITGA2B gene promoter-driven human αIIb cDNA into patient blood stem cells, we observed new protein expression that formed the correct αIIbβ3 complex on the surface of megakaryocytes, , thus providing proof‑of-principle of the feasibility for a potential therapeutic approach for treating GT patients and other patients with diseases affecting platelet function.
To demonstrate that this approach could be used effectively, we performed studies in a canine model GT. Dogs treated with this technology displayed improved hemostatic activity, reduced blood loss, and bleeding times decreased to normal. From these results, we believe that this gene therapy has potential for treating both GT and other inherited platelet defects.
We are currently preparing to pursue a first in humans Phase I clinical trial hopefully to correct Glanzmann’s Thrombasthenia (GT) in humans using gene replacement therapy. We have been made aware of a number of patients interested in participating in this trial using HSC-LV gene therapy. Members of curegt.org representing these patients visited the research facilities at medical college of Wisconsin in 2022. Pending results of our current Hemophilia A Phase I trial, we are moving ahead with development of a Phase I study for Glanzmann Thrombasthenia, targeted to begin in late 2025.