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

Christian Medical College, Vellore, India

Status and phase

Completed

Phase 1

Conditions

Hemophilia A

Treatments

Biological: Auto CD34+PBSC transduced with a lentiviral vector encoding a novel coagulation factor VIII transgene

Study type

Interventional

Funder types

Other

Identifiers

NCT05265767

CSCR-CMC/FVIII LVGT/2018

Details and patient eligibility

About

Factor VIII (FVIII) is a large plasma glycoprotein that participates in blood coagulation. Loss of circulating FVIII activity due to mutations within the F8 gene results in the X-linked, recessive bleeding disorder hemophilia A. The clinical presentation ranges from a mild to severe bleeding phenotype that correlates with the patient's residual plasma FVIII activity level.

Current state of the art treatment entails frequent infusion of FVIII protein. However, several limitations remain to treating hemophilia A, which are 1) access to FVIII-replacement products (currently <30% of the world population is treated adequately, access is highly restricted in India), 2) high burden of compliance with treatment protocols particularly in children 3) the expense of FVIII-replacement products, 4) the development of humoral anti-FVIII immune responses that block FVIII activity and limit treatment efficacy and 5) morbidity due to crippling musculoskeletal disease when inadequately treated. Several newer hemostasis agents are being developed but like the recombinant Clotting Factor Concentrate (CFC) from the 1990s, these are also not likely to be made available in India for many years. Currently, the only cure for hemophilia A is orthotopic liver transplantation.

Full description

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.

Enrollment

6 patients

Sex

Male

Ages

18 to 45 years old

Volunteers

No Healthy Volunteers

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.