Expanded Access Protocol for Gene Therapy Utilizing shmiR Lentivirus Vector to Induce Fetal Hemoglobin in Sickle Cell Disease (GRASP-EA)

A promising approach for the treatment of genetic diseases is called gene therapy. Gene therapy is a relatively new field of medicine in which genetic material (mostly DNA) in the patient is changed to treat his or her own disease. In gene therapy, we introduce new genetic material in order to fix or replace the patient's disease gene, with the goal of curing the disease. The procedure is similar to a bone marrow transplant, in that the patient'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 stem cells for the transplant, the patient's own blood stem cells are given back after the new genetic material has been introduced into those cells. This approach has the advantage of eliminating any risk of graft versus host disease (GVHD), reducing the risk of graft rejection, and may also allow less chemotherapy to be utilized for the conditioning portion of the transplant procedure. To introduce new genetic material into the patient's own blood stem cells we use a modified version of a virus (called a 'vector') that efficiently inserts the "correcting" genetic material into the cells. The vector is a specialized biological medicine that has been formulated for use in human beings.

Fetal hemoglobin (HbF) is a healthy, non-sickling kind of hemoglobin. The investigators have 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 amount of fetal hemoglobin while simultaneously reducing the amount of sickle hemoglobin in their blood, specifically the amount in red blood cells where sickle hemoglobin causes damage to the cell, and therefore potentially cure or significantly improve the condition. The gene we are targeting for change in this study that controls the level of fetal hemoglobin is called BCL11A.

36 patients have received the gene therapy product, and the data so far has shown that the treatment has not caused any unexpected safety problems, and that it increases HbF within the red cells.

Study Overview

• Status: Temporarily not available
• Conditions: Sickle Cell Disease
• Intervention / Treatment: Biological: Autologous CD34+ HSC cells transduced with the lentiviral vector containing a shRNA targeting BCL11a

Detailed Description

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.

• Study Type: Expanded Access
• Expanded Access Type: Intermediate-size Population

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: N/A

Description

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.

Study Plan

How is the study designed?

Collaborators and Investigators

• Sponsor: David Williams

Study record dates

Study Registration Dates

• First Submitted: May 28, 2026
• First Submitted That Met QC Criteria: June 5, 2026
• First Posted (Actual): June 11, 2026

Study Record Updates

• Last Update Posted (Actual): June 11, 2026
• Last Update Submitted That Met QC Criteria: June 5, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: gene therapy; BCL11A; lentivirus vector; fetal hemoglobin
• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Hematologic Diseases; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hemoglobinopathies; Thalassemia; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hemic and Lymphatic Diseases; Anemia, Sickle Cell; beta-Thalassemia
• Other Study ID Numbers: P00054465