Gene Therapy Trial for Platelet Derived Factor VIII Production in Hemophilia A

This is an open label, nonrandomized, single center, phase I cohort study, involving reduced intensity conditioning, followed by a single infusion of autologous CD34+PBSC, transduced with a lentiviral vector (-889ITGA2B-BDDFVIII-WPTS (MUT6)(VSVg)) also known as (Pleightlet(MUT6)) encoding the B domain deleted from of human coagulation factor VIII (BDDFVIII) in up to five hemophilia A patients with a history of FVIII inhibitors (≥0.6BU) .

Inclusion criteria

Study population will include: adult males >18 years of age with a diagnosis of severe hemophilia A and currently active or a history of FVIII inhibitors (≥0.6 BU). Females will be excluded because hemophilia A is an X-linked disorder that is extremely rare in females.

• Confirmed diagnosis of severe hemophilia A by undetectable plasma factor VIII:C by a one-stage PTT-based assay and coatest chromogenic factor VIII assay. Subjects with currently active or a history of positive FVIII inhibitor titers (≥0.6 BU) irrespective of their titer or current inhibitor status will be included for enrollment.
• Subject may be prescribed prophylactic therapy with factor VIII bypassing agents or factor VIII mimetics prior to referral for inclusion in the study.
• Subjects who are treated on demand using factor VIII bypassing agents must have a history of four or more bleeding episodes requiring treatment in the six-month period prior to referral for inclusion in the study.
• Adequate bone marrow reserve as demonstrated by ANC >1.5/cu.mm; Hemoglobin >9g/dL; Platelets >100,000/microliter.
• Adequate renal function, defined as creatinine clearance>60 ml/min (Cockroft-Gault formula)
• Adequate liver function, defined as defined as total bilirubin ≤1.5 times the upper limit of normal (ULN) (excluding Gilbert's syndrome), both AST and ALT ≤3 times ULN at the time of screening, and no clinical signs or known laboratory/radiographic evidence consistent with cirrhosis.
• Subject must sign an informed consent after explanation of the study and having questions answered.
• Subject must be willing and able to document type of bleeding episodes and treatment in a paper or electronic diary during the study.
• Subject must be willing to return for regular follow-up visits during the 15-year study.

Exclusion criteria

• A potential subject who meets any of the following exclusion criteria is ineligible to participate in the study.

• Therapy with factor VIII with the intent of immune tolerance induction within 30 days prior to inclusion within the study.
• Enrollment in another interventional clinical trial within 60 days prior to study inclusion.
• Medical contraindication to PBSC cytokine mobilization, use of GCSF, PBSC apheresis procedure or conditioning regimen.
• Medically significant organ dysfunction that would prevent compliance with conditioning or would severely limit the probability of survival based on clinical status.
• Those with a known co-existing clinically significant thrombophilic disorder, or as determined by the presence of any of the below identified on screening laboratory assessments:

• FV Leiden
• Protein S deficiency
• Protein C deficiency
• Prothrombin mutation (G20210A)
• D-dimer >3 x the upper limit of normal (ULN) at Screening All known patients with the above and any patient with a personal or significant family history of thrombotic events (DVT, PE, arterial clots) as deemed by the principal investigator will be screened for the above disorders.
• Active invasive malignancy (Non-melanoma skin cancers and carcinoma in situ are not excluded).
• Known bone marrow disorders or abnormal bone marrow cytogenetics.
• Fertile males who are unwilling to use contraceptive techniques during and for the twelve months following treatment.
• Life expectancy severely limited by disease(s) other than hemophilia A.
• Patients with HIV, hepatitis B, hepatitis C (with an AST/ALT > 3 times the upper limit of normal).
• Other active infectious disease that is a contraindicat ion for immunosuppressive therapy.
• Patients who have elective surgery scheduled during the study period.