Lentiviral gene therapy reverts GPIX expression and phenotype in Bernard-Soulier syndrome type C

Bernard-Soulier syndrome (BSS) is a bleeding disorder associated with abnormal platelets, due to mutations in one of three genes: GpIba (BSS-type A), GpIbb (BSS-type B), or GpIX (BSS-type C) that are assembled in a glycoprotein complex on the surface of platelet membrane.1 Two GPIb-IX adducts bind to one GpV molecule, forming the trimolecular GPIb-IX-V complex. The latter is the main receptor of von Willebrand factor.2 In addition, thrombin, the final activated factor of the coagulation cascade, can bind with high affinity to GpIba.3,4 Interaction of the GPIb-IX-V complex to von Willebrand factor allows platelets to stick to the blood vessel wall at the site of the injury. These platelets form clots, plugging holes in the blood vessels to help stop bleeding. The presence of about one hundred natural mutations in GpIba, GpIbb, or GpIX prevents the formation or the complex’s interaction with von Willebrand factor, leading to the excessive bleeding characteristic of BSS. The therapy of this genetic disorder is usually symptomatic, based on platelet transfusion and the use of hemostatic agents such as tranexamic acid, desmopressin, oral contraceptives during menses, and recombinant FVIIa.5,6 More aggressive therapies, such as bone marrow transplantation, have also been employed in the most severe cases.5 In this problematic scenario, the study by Martinez-Navajas and colleagues represents a first pre-clinical model to correct BSS with gene therapy.