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.
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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
6
Auto CD34+PBSC transduced with a lentiviral vector encoding a novel coagulation factor VIII transgene administered by IV infusion following conditioning regimen.
Christian Medical College Vellore Ranipet Campus
Vellore, Tamil Nadu, India
Number of study participants experiencing serious adverse events (SAEs) following treatment through 12 weeks.
As assessed by physical examination, vital signs, clinical labs, and FVIII inhibitor levels (Bethesda assay). Serious adverse event (SAE) is an AE resulting in any of the following outcomes: death; Life-threatening event; Required or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly.
Time frame: Percentage of patients experiencing SAEs following 12 weeks of treatment
Severity of serious adverse events following administration of CD68-ET3-LV CD34+ as assessed by NCI Common Toxicity Criteria for Adverse Events (CTCAE) Version 5.0.
Serious adverse events severity assessment
Time frame: Assessement of severity of SAE through 12 weeks after treatment
Duration of the serious adverse events following administration of CD68-ET3-LV CD34+.
As assessed by stop and end dates of the SAEs
Time frame: Assessment of duration of SAEs after 12 weeks of treatment
Time to absolute neutrophil count (ANC) recovery.
Time to ANC recovery (the first day a neutrophil count is \>0.5 x 109/L (\>500/µL) on three consecutive days) following busulfan/ anti-thymocyte globulin conditioning and infusion of autologous CD34+ hematopoietic stem and progenitor cells (HSPC) transduced with CD68-ET3-LV.
Time frame: Measurement of ANC upto 5 years
Time to platelet recovery
Time to platelet recovery (the first day a platelet count is \> 50,000/µL on three consecutive days without platelet transfusions during the prior 7 days) following infusion of autologous CD34+ cells transduced with CD68-ET3-LV.
Time frame: Measured of platelet recovery upto 5 years
Anti-human factor VIII inhibitor titer
Assessed via Bethesda assay
Time frame: Measured of FVIII inhibitor titer upto 5 years
Immune response to ET3 as measured by modified Bethesda assay incorporating ET3i spiked into FVIII-deficient plasma
Immune response to ET3
Time frame: Measured of Immune response to ET3 for up to 5 years
Vector copy number of circulating genetically modified cells as determined by real time Polymerase Chain Reaction (PCR)
Vector copy number determined via real time PCR
Time frame: Measured of Vector copy number by PCR upto 5 years
To evaluate FVIII activity after Autologous Hematopoietic Stem Cell Transplantation (HSCT) with CD68ET3-LV transduced CD34+ cells through measurement of plasma FVIII activity levels.
Evaluate FVIII activity
Time frame: Measurement of FVIII activity (assay) upto 5 years
To evaluate the impact of autologous HSCT with CD68ET3-LV transduced CD34+ cells on bleeding phenotype as measured by frequency of bleeding episodes and clotting factor concentrate (CFC) usage.
Evaluate the impact of autologous HSCT with CD68ET3-LV transduced CD34+ cells
Time frame: Measured of frequency of bleeding episodes and CFC usage upto 5 years
To evaluate the relationship between FVIII activity level and engraftment of CD68ET3-LV modified cells.
Evaluate correlation between FVIII activity in % level and engraftment of ANC measured in per cubic milliliter (cumm) Platelets values in per cumm
Time frame: Evaluation of relationship between FVIII activity and engraftment upto 5 years
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