Gene Therapy for Sickle Cell Disease

(GRASP Trial)

Recruiting at 13 trial locations

Overseen By Lauren Holmes

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: David Williams

Must not be taking: Hydroxyurea

Disqualifiers: Active infection, Malignancy, Stroke, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

25 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial uses gene therapy to treat patients with severe Sickle Cell Disease by modifying their own blood stem cells. The treatment aims to increase healthy hemoglobin levels by changing a specific gene. This approach could reduce painful episodes and improve overall health without needing a donor.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, it mentions that patients on a chronic transfusion regimen for stroke prevention are not eligible, which might imply some restrictions. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of this treatment for sickle cell disease?

Research shows that using a lentiviral vector to target BCL11A in stem cells can increase fetal hemoglobin levels, which helps reduce the harmful effects of sickle cell disease. Studies in both human cells and animal models have demonstrated that this approach is safe and effective, with long-term benefits and no significant toxicity. ^{1 2 3 4 5}

Is gene therapy targeting BCL11A safe for humans?

Preclinical studies show that gene therapy targeting BCL11A, using a lentiviral vector, is non-toxic and safe in animal models, with no increased risk of harmful genetic changes. This supports its potential safety for human clinical trials. ^{1 2 4 5 6}

How does this gene therapy treatment for sickle cell disease differ from other treatments?

This treatment is unique because it uses a lentiviral vector to deliver a short hairpin RNA (shRNA) that specifically targets and reduces the expression of BCL11A, a protein that suppresses fetal hemoglobin production. By reactivating fetal hemoglobin, it reduces the harmful effects of sickle hemoglobin, offering a novel approach compared to traditional treatments that do not target this genetic mechanism. ^{1 3 4 5 7}

Research Team

David Williams

Principal Investigator

Boston Children&#39;s Hospital

Eligibility Criteria

This trial is for people aged 13-40 with severe sickle cell disease (HbSS or HbS/β0 thalassemia) who've had at least 4 pain crises in the last 2 years. They need good organ function, no matching bone marrow donor, and can't be on chronic blood transfusions or have a history of stroke, certain infections like HIV/Hepatitis, liver issues from iron overload, or other conditions that could interfere with treatment.

Inclusion Criteria

I am between 13 and 40 years old.

I have had 4 or more severe pain episodes in the last 2 years.

My organs are working well and I am in good health.

Exclusion Criteria

I have had a stem cell transplant from a donor.

I have an abnormal TCD history and am now on hydroxyurea.

I have severe blood vessel problems in my brain.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-treatment

Patients receive blood transfusions for at least 3 months to achieve a HbS level ≤ 30% before stem cell collection

12 weeks

Stem Cell Collection and Transduction

Peripheral stem cell mobilization and collection by apheresis, followed by transduction with lentiviral vector

2-4 weeks

Conditioning and Infusion

Myeloablative conditioning with busulfan followed by infusion of transduced cells

1 week

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Treatment Details

Interventions

• Autologous CD34+ HSC cells transduced with the lentiviral vector containing a shRNA targeting BCL11a

Trial Overview The study tests gene therapy to increase fetal hemoglobin which doesn't sickle. Patients' own stem cells are modified using a virus vector targeting BCL11A gene to reduce sickling hemoglobin levels. This could potentially cure or improve their condition without needing a donor and may use less chemotherapy.

Participant Groups

Group I: Treatment Arm Experimental Treatment 1 Intervention

Open-label, non-randomized, single arm study of a single infusion of autologous CD34+ HSC cells transduced with the lentiviral vector containing a shRNA targeting BCL11a.

Who Is Running the Clinical Trial?

David Williams

Lead Sponsor

Trials

5

Recruited

60+

California Institute for Regenerative Medicine (CIRM)

Collaborator

Trials

70

Recruited

3,300+

bluebird bio

Industry Sponsor

Trials

21

Recruited

2,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Blood and Marrow Transplant Clinical Trials Network

Collaborator

Trials

51

Recruited

14,600+

Findings from Research

The BCH-BB694 lentiviral vector effectively reactivates fetal hemoglobin production while reducing harmful adult sickle hemoglobin in sickle cell disease, showing a 3- to 5-fold increase in fetal hemoglobin levels in transduced cells.

Preclinical studies indicate that BCH-BB694 is non-toxic and can be produced at a clinically relevant scale, supporting its potential for safe and effective use in human trials for treating sickle cell disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical Evaluation of a Novel Lentiviral Vector Driving Lineage-Specific BCL11A Knockdown for Sickle Cell Gene Therapy. Brendel, C., Negre, O., Rothe, M., et al.[2020]

References

1. United States pubmed.ncbi.nlm.nih.gov

BCL11A enhancer-edited hematopoietic stem cells persist in rhesus monkeys without toxicity. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Bone Marrow as a Hematopoietic Stem Cell Source for Gene Therapy in Sickle Cell Disease: Evidence from Rhesus and SCD Patients. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Novel lentiviral vectors for gene therapy of sickle cell disease combining gene addition and gene silencing strategies. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Preclinical Evaluation of a Novel Lentiviral Vector Driving Lineage-Specific BCL11A Knockdown for Sickle Cell Gene Therapy. [2020]

5. United States pubmed.ncbi.nlm.nih.gov

Long-Term Engraftment and Fetal Globin Induction upon BCL11A Gene Editing in Bone-Marrow-Derived CD34+ Hematopoietic Stem and Progenitor Cells. [2020]

6. United States pubmed.ncbi.nlm.nih.gov

Development of a double shmiR lentivirus effectively targeting both BCL11A and ZNF410 for enhanced induction of fetal hemoglobin to treat β-hemoglobinopathies. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Lineage-specific BCL11A knockdown circumvents toxicities and reverses sickle phenotype. [2019]