A promising approach for the treatment of genetic diseases is called gene therapy. Genetherapy is a relatively new field of medicine in which genetic material (mostly DNA) inthe patient is changed to treat his or her own disease. In gene therapy, we introduce newgenetic material in order to fix or replace the patient's disease gene, with the goal ofcuring the disease. The procedure is similar to a bone marrow transplant, in that thepatient's malfunctioning blood stem cells are reduced or eliminated using chemotherapy,but it is different because instead of using a different person's (donor) blood stemcells for the transplant, the patient's own blood stem cells are given back after the newgenetic material has been introduced into those cells. This approach has the advantage ofeliminating any risk of graft versus host disease (GVHD), reducing the risk of graftrejection, and may also allow less chemotherapy to be utilized for the conditioningportion of the transplant procedure. To introduce new genetic material into the patient'sown blood stem cells we use a modified version of a virus (called a 'vector') thatefficiently inserts the "correcting" genetic material into the cells. The vector is aspecialized biological medicine that has been formulated for use in human beings.Fetal hemoglobin (HbF) is a healthy, non-sickling kind of hemoglobin. The investigatorshave discovered a gene that is very important in controlling the amount of HbF.Decreasing the expression of this gene in sickle cell patients could increase the amountof fetal hemoglobin while simultaneously reducing the amount of sickle hemoglobin intheir blood, specifically the amount in red blood cells where sickle hemoglobin causesdamage to the cell, and therefore potentially cure or significantly improve thecondition. The gene we are targeting for change in this study that controls the level offetal hemoglobin is called BCL11A.36 patients have received the gene therapy product, and the data so far has shown thatthe treatment has not caused any unexpected safety problems, and that it increases HbFwithin the red cells.
This is an expanded access protocol (EAP) involving a single infusion of autologous bone
marrow derived CD34+ HSC cells transduced with the lentiviral vector containing a
short-hairpin RNA targeting BCL11A.
The primary purpose of this EAP is to provide access to the treatment for eligible
patients with SCD who have an unmet clinical need, as determined by the treating
physician, and who are unable to enroll in an appropriate clinical trial or are
ineligible to receive an FDA-approved gene therapy product.
After meeting the initial eligibility criteria, participants will undergo mobilization
and collection of CD34⁺ hematopoietic stem and progenitor cells (HSPCs). Participants
will receive red blood cell transfusions for at least two months prior to stem cell
collection, with a goal of reducing the HbS level to ≤ 30% before mobilization. The
collected cells will be divided into two fractions: one for drug product manufacturing,
and the other stored as a back-up product for potential rescue use. Gene modification
procedures will be performed on the selected CD34⁺ cell population, and the resulting
drug product will be cryopreserved until infusion.
Participants will receive myeloablative conditioning with busulfan on days -5 through -2,
followed by a single infusion of the transduced autologous cells on Day 0.
After discharge from the transplant admission, participants will continue follow-up
visits for two years at their treating physician's center according to usual clinical
care. Safety data and selected clinical outcome data arising during the course of routine
clinical care may be collected descriptively.
This EAP will end when this treatment is approved by the FDA and is commercially
available for patients with SCD, or the IND Sponsor terminates the program.
Biological: Autologous CD34+ HSC cells transduced with the lentiviral vector containing a shRNA targeting BCL11a
A single infusion of autologous CD34+ HSC cells transduced with the lentiviral vector
containing a shRNA targeting BCL11a
Inclusion Criteria:
1. Age ≥13-55 years.
2. Patients with severe phenotype sickle cell disease (HbSS and other genotypes
including HbSC); severity defined by VOE events in previous 2 years prior to
enrollment on EAP
a. At least 4 VOEs within the past 24 months prior to consent defined as: i. severe
painful event with no medically determined cause other than vaso-occlusion requiring
≥24 hours in a hospital facility for medical management OR 2 visits to a day unit or
emergency room over 72 hours with both visits requiring parenteral opioids and/or
parenteral non-steroidal agents ii. acute chest syndrome defined as a new infiltrate
on a chest X-ray and new concomitant hypoxia requiring hospital admission and not
attributable to another cause iii. Priapism episodes requiring hospitalizations
3. Patients who meet the above criteria for disease severity, but have experienced poor
mobilization, RBC alloimmunization as described below:
a. Poor mobilization response to plerixafor in other trials i. Patients who were
enrolled in commercial GT or trials who failed to mobilize or failed to collect
sufficient stem cells to generate a drug product can be entered in the trial.
Patients will be evaluated for opportunities to improve stem cell collection
efficiency and by using motixafortide as a mobilization agents
b. RBC alloimmunized and/or history of hyperhemolysis i. History of allo-antibodies,
DHTR or hyperhemolysis limiting the ability to fully undergo preparative red cell
exchanges for mobilization and collection or for conditioning and transplant.
Patients would be evaluated for the ability to secure at least 8 units of red blood
cells for peri-SCT support.
4. Adequate hematologic parameters (regardless of therapy) including:
1. White blood cell (WBC) count within the range of 2.5 - 25.0 x 109 /L
2. Hemoglobin within the range of 5 - 11 g/dL
3. Platelet count above 150 x 109 /L
5. Adequate organ function and performance status:
1. Karnofsky/Lansky performance status ≥ 80%.
2. Calculated creatinine clearance or GFR >/= 40 mL/min/1.73 m2.
3. Aspartate transaminase, alanine transaminase, and direct bilirubin value < 3
times the upper limit of normal (ULN) (per institutional upper limit of
normal).
4. DLCO (corrected for hemoglobin), FEV1, and FVC > 50% of predicted
5. Left ventricular ejection fraction > 40% or shortening fraction > 25%
6. Parental/guardian/participant signed informed consent
Exclusion Criteria:
1. Patients who have concomitant condition or illness including, but not limited to:
1. Ongoing or active infection
2. Active malignancy
3. Major surgery in the past 30 days
4. Medical/psychiatric illness/social situations that would limit compliance with
study requirements as determined by the treating physician.
2. Patients with chronic pain defined as pain requiring opioids on a majority of days
in the past 6 months before consent or patients taking long-acting daily opioids for
longer than 6 months prior to enrollment or patients requiring blood transfusion to
manage chronic pain prior to consent.
3. Patients with history of overt CNS stroke at any time. Patients with imaging
evidence of silent stroke but not on a chronic transfusion regimen are not excluded.
4. Receiving a chronic transfusion regimen for primary or secondary stroke prophylaxis.
5. Patients with history of abnormal TCD (measured with a timed average maximum mean
velocity of ≥ 200 cm/second in the terminal portion of the internal carotid or
proximal portion of middle cerebral artery or if the imagining TCD method is used, >
185 cm/second plus evidence of intracranial vasculopathy) who were ever on
transfusions and subsequently transitioned to hydroxyurea.
6. Patients with severe cerebral vasculopathy (defined by Moya-moya disease or
occlusion or stenosis in the circle of Willis. Note: patients who have had surgical
correction are not eligible).
7. Isolated recurrent priapism unresponsive to medical and surgical therapies in the
absence of other qualifying VOE complications that meet inclusion criteria.
8. Contraindication to administration of conditioning medication (busulfan).
9. Patients who have undergone allogeneic hematopoietic stem cell transplant
previously.
10. Known myelodysplasia of the bone marrow or abnormal bone marrow cytogenetics. For
participants undergoing baseline bone marrow evaluation as part of this EAP
(patients >35 years of age), evidence of a myeloid malignancy, myelodysplastic
syndrome, or other clinically significant bone marrow abnormality, including
abnormal cytogenetics or molecular findings, that in the opinion of the treating
physician would represent a contraindication to proceeding with gene therapy.
11. Liver MRI to document hepatic iron content is required for participants who have
received ≥ 20 packed red blood cell transfusions (cumulative). Participants who have
hepatic iron content ≥ 9 mg Fe/g liver dry weight by liver MRI must have a liver
biopsy and histological examination/documentation of the absence of cirrhosis,
moderate or severe portal fibrosis, bridging fibrosis, and active hepatitis (≤ 180
days prior to initiation of transplant conditioning). The degree of portal fibrosis
and the absence of bridging fibrosis will be determined using the histological
grading and staging scale as described by Ishak and colleagues (1995). Repeat liver
MRI is encouraged in the event the interval between consent and initiation of BU
conditioning exceeds 180 days).
12. Evidence of active HIV infection, active HTLV 2 infection, active hepatitis B
infection, or active hepatitis C infection.
13. Receipt of an investigational study drug or procedure within 90 days of study
enrollment.
14. Prior receipt of a genetically modified product.
15. Pregnancy, or breastfeeding in a postpartum female, or absence of adequate
contraception for fertile participants. Females of child-bearing potential must
agree to use a medically acceptable method of birth control such as oral
contraceptive, intrauterine device, barrier and spermicide, or contraceptive
implant/injection from screening through at least 6 months after drug product
infusion. Male participants must agree to use effective contraception (including
condoms) from screening through at least 6 months after drug product infusion.
16. Presence of a genetically-determined hypercoagulable state or personal history of
prior VTE (deep vein thrombosis or pulmonary embolism) that, in the opinion of the
treating physician, would represent a contraindication to proceed with central line
placement and study events.
Boston Children's Hospital
Boston, Massachusetts, United States
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