Hematopoietic Stem Cell Transplantation Gene Therapy for Treatment of Severe Hemophilia A

Eligible subjects will undergo (Cluster of Differentiation) CD34+ hematopoietic stem cell collection. These cells will be transduced ex vivo with (Cluster of Differentiation) CD68-ET3 lentiviral vector and subsequently, following a conditioning regimen, the transduced cells will be infused to patients. After completion of study treatment, patients are followed up periodically for up to 15 years.

Inclusion criteria

• Able to provide informed consent for the protocol approved by the Institutional Review Board.
• Male subjects who are ≥18 years of age and < 45 years of age.
• Diagnosis of severe hemophilia A (<1 IU/dl factor VIII activity).
• Documented history of more than 100 exposures of factor VIII treatment.
• Average of at least 3 bleeds requiring treatment per year over the prior three years, at least 3 bleeds per year during the 3 years preceding the initiation of prophylaxis, or evidence of joint damage (knee, elbow or ankle) on physical or radiographic examination thought to be related to hemophilia.
• Performance status (Karnofsky score) of at least 70.
• Willing and able to comply with the requirements of the protocol.

Exclusion criteria

• History of spontaneous central nervous system bleeding within the last 5 years.
• Significant organ dysfunction which could interfere with outcome of therapy such as: -
• Cardiac: There should be no evidence of significant cardiac dysfunction (resting left ventricular ejection fraction of < 50%) and no cardiomegaly. There should not be uncontrollable hypertension.
• Renal: Glomerular Filtration Rate (GFR) < 60 ml/min/1.73m2 as calculated using the Cockcroft-Gault equation.
• Hepatic: There should be no evidence of hepatic dysfunction which is defined as a serum bilirubin of > 1.5 mg/dl and Aspartate Amino Transferase (AST) / Alanine Amino Transferase (ALT) > 3X the upper limit of normal,
• Hematologic: Absolute neutrophil counts (ANC) < 1000/mm3 and platelets counts < 150,000/μL.
• Pulmonary function with a corrected Diffusing Capacity of lung for Carbon Monoxide (DLCO) of < 50% predicted
• History of a FVIII inhibitor (>0.6 Bethesda Units/ml) including at least 2 measurements over the preceding 5 years or any single titer >5 Bethesda Units (BU) /ml.
• Previous stem cell transplant.
• HIV positive.
• Evidence of hepatitis B active infection or chronic carrier
• Evidence of chronic hepatitis C infection. Absence of chronic infection will be documented with at least 2 negative viral loads at least 6 months apart.
• Diagnosis of a bleeding disorder other than hemophilia A
• Use of medication(s) that can affect hemostasis (e.g. aspirin and non- cyclooxygenase (COX-2) selective non-steroid anti-inflammatory drugs).
• History of cancer or familial cancer syndromes
• Any condition in the opinion of the principle investigator that will negatively impact the subject's ability to safely undergo an autologous stem cell transplant.
• Any reason in the opinion of the principle investigator that will negatively impact the subject's ability to complete the clinical trial per the trial protocol.