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

Eligibility Criteria

• 1. 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.
• 2. Subject may be prescribed prophylactic therapy with factor VIII bypassing agents or factor VIII mimetics prior to referral for inclusion in the study.
• 3. 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.
• 4. Adequate bone marrow reserve as demonstrated by ANC \>1.5/cu.mm; Hemoglobin \>9g/dL; Platelets \>100,000/microliter.
• 5. Adequate renal function, defined as creatinine clearance\>60 ml/min (Cockroft-Gault formula)
• 6. 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.
• 7. Subject must sign an informed consent after explanation of the study and having questions answered.
• 8. Subject must be willing and able to document type of bleeding episodes and treatment in a paper or electronic diary during the study.
• 9. Subject must be willing to return for regular follow-up visits during the 15-year study.
• * A potential subject who meets any of the following exclusion criteria is ineligible to participate in the study.
• 1. Therapy with factor VIII with the intent of immune tolerance induction within 30 days prior to inclusion within the study.
• 2. Enrollment in another interventional clinical trial within 60 days prior to study inclusion.
• 3. Medical contraindication to PBSC cytokine mobilization, use of GCSF, PBSC apheresis procedure or conditioning regimen.
• 4. Medically significant organ dysfunction that would prevent compliance with conditioning or would severely limit the probability of survival based on clinical status.
• 5. 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.
• 6. Active invasive malignancy (Non-melanoma skin cancers and carcinoma in situ are not excluded).
• 7. Known bone marrow disorders or abnormal bone marrow cytogenetics.
• 8. Fertile males who are unwilling to use contraceptive techniques during and for the twelve months following treatment.
• 9. Life expectancy severely limited by disease(s) other than hemophilia A.
• 10. Patients with HIV, hepatitis B, hepatitis C (with an AST/ALT \> 3 times the upper limit of normal).
• 11. Other active infectious disease that is a contraindicat ion for immunosuppressive therapy.
• 12. Patients who have elective surgery scheduled during the study period.