Stem Cell Gene Therapy for Sickle Cell Disease

Overseen By Gary Schiller, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Donald B. Kohn, M.D.

Must be taking: Hydroxyurea

Disqualifiers: HLA-identical donor, Hypertension, HIV, others

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

Compensation: Varies

Number of Visits: 3

Duration: 1 week

4 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a new treatment for adults with severe sickle cell disease using their own modified blood cells. The treatment aims to fix the genetic problem causing sickle cell disease and help patients produce healthy red blood cells. This approach could be better than current treatments and avoid complications from donor transplants. The new therapy involves modifying the patient's own blood cells to correct the genetic issue.

Will I have to stop taking my current medications?

The trial requires that participants stop taking hydroxyurea (a medication for sickle cell disease) at least 30 days before collecting stem cells. The protocol does not specify about other medications, so it's best to discuss your current medications with the trial team.

What data supports the effectiveness of the treatment βAS3-FB vector transduced peripheral blood CD34+ cells for sickle cell disease?

Research shows that using a lentiviral vector to introduce an anti-sickling gene into blood stem cells can significantly reduce the sickling of red blood cells in sickle cell disease. This approach has been effective in preclinical models, suggesting it could help manage the disease in patients. ^{1 2 3 4 5}

Is stem cell gene therapy for sickle cell disease safe for humans?

Research shows that stem cell gene therapy for sickle cell disease, including methods using plerixafor and gene correction strategies, has been generally safe in preclinical and early clinical studies. There were no significant safety concerns like abnormal blood cell development or cancer risk, although some patients experienced mild adverse events. ^{1 4 6 7 8}

How is the stem cell gene therapy treatment for sickle cell disease different from other treatments?

This treatment uses a lentiviral vector to introduce a modified gene into the patient's own stem cells, which helps produce a form of hemoglobin that reduces sickling of red blood cells. Unlike traditional treatments that manage symptoms, this approach aims to correct the underlying genetic defect, potentially offering a more lasting solution. ^{2 5 6 9 10}

Research Team

Gary Schiller, MD

Principal Investigator

University of California, Los Angeles

Donald Kohn, MD

Principal Investigator

University of California, Los Angeles

Eligibility Criteria

Adults with severe sickle cell disease who have had complications like pain crises, stroke, or acute chest syndrome despite treatment can join this trial. They must not be pregnant, have HIV/HCV/HTLV-1/hepatitis B/Cancer, and should not have a suitable sibling donor for transplant.

Inclusion Criteria

I do not have a perfect match donor for a stem cell transplant or I refuse to have one.

My condition did not improve after taking hydroxyurea for 3 months.

I have been hospitalized for sickle cell pain crises at least twice.

Exclusion Criteria

I don't have any other cancer or active infections.

My blood pressure is high (>135/95) despite taking medication.

I do not have active infections like HIV, Hepatitis B/C, HTLV-1, CMV, or parvovirus B19.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-treatment

Participants receive chronic red blood cell transfusions prior to stem cell collection and transplant

4-6 weeks

Stem Cell Collection and Modification

Peripheral blood stem cells are collected using plerixafor mobilization and apheresis, then transduced with the Lenti/G-βAS3-FB lentiviral vector

2 weeks

Treatment

Participants receive marrow cytoreduction with busulfan followed by infusion of gene-modified cells

1 week

Follow-up

Participants are monitored for safety and effectiveness after treatment, with active follow-up for 2 years

24 months

Visits at intervals of no more than 3 months

Long-term Follow-up

Participants are offered enrollment into a long-term follow-up study during years 3-15

12 years

Treatment Details

Interventions

• βAS3-FB vector transduced peripheral blood CD34+ cells

Trial Overview The trial is testing a gene therapy where patients' own blood stem cells are modified with the βAS3-FB vector to potentially treat sickle cell disease. It's in Phase I to check safety and initial effectiveness.

Participant Groups

Group I: βAS3-FB vector transduced peripheral blood CD34+ cells Experimental Treatment 1 Intervention

This is a single arm study without randomization. All subjects will receive the intervention of BetaAS3 lentiviral vector-modified autologous peripheral blood stem cell transplant.

Who Is Running the Clinical Trial?

Donald B. Kohn, M.D.

Lead Sponsor

Trials

2

Recruited

10+

California Institute for Regenerative Medicine (CIRM)

Collaborator

Trials

70

Recruited

3,300+

Findings from Research

A new therapeutic approach combining lentiviral gene addition and CRISPR-Cas9 strategies shows promise for treating sickle cell disease (SCD) by allowing for effective gene editing and expression of anti-sickling hemoglobins with lower vector copy numbers.

This method not only enhances the levels of beneficial hemoglobins but also reduces the risk of genotoxicity associated with high vector amounts, making it a safer option for patients with SCD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of lentiviral and genome editing technologies for the treatment of sickle cell disease. Ramadier, S., Chalumeau, A., Felix, T., et al.[2023]

A CRISPR-Cas9 gene correction strategy demonstrated up to 60% correction of the sickle cell disease-causing mutation in patient-derived hematopoietic stem cells, showing promising efficacy for potential treatment.

Preclinical studies in mice showed that the corrected cells engrafted successfully without signs of abnormal blood cell formation or tumor development, indicating a favorable safety profile for this gene therapy approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of β-globin gene correction in human hematopoietic stem cells as a potential durable treatment for sickle cell disease. Lattanzi, A., Camarena, J., Lahiri, P., et al.[2022]

In a phase I study involving 15 patients with sickle cell disease, the mobilizing agent plerixafor was found to be well tolerated, with a low rate of serious adverse events, although it did not consistently achieve the desired mobilization of CD34+ hematopoietic progenitor cells.

The study suggested that prior treatment with hydroxyurea may have limited the effectiveness of plerixafor in mobilizing CD34+ cells, indicating that adjustments in hydroxyurea administration may be necessary for future trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of plerixafor dose escalation for the mobilization of CD34+ hematopoietic progenitor cells in patients with sickle cell disease: interim results. Boulad, F., Shore, T., van Besien, K., et al.[2021]

A novel hybrid reprogramming vector was developed to efficiently generate patient-specific induced pluripotent stem cells (iPSCs) from sickle cell disease (SCD) patients, achieving high efficiency without off-target modifications.

Using CRISPR/Cas9, the sickle cell mutation was corrected in these iPSCs with a correction efficiency of up to 67.9%, and whole-genome sequencing confirmed the absence of unintended genetic changes, indicating a safe approach for potential gene therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel HDAd/EBV Reprogramming Vector and Highly Efficient Ad/CRISPR-Cas Sickle Cell Disease Gene Correction. Li, C., Ding, L., Sun, CW., et al.[2018]

References

1. 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]

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

Pre-clinical Development of a Lentiviral Vector Expressing the Anti-sickling βAS3 Globin for Gene Therapy for Sickle Cell Disease. [2020]

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

A novel human gamma-globin gene vector for genetic correction of sickle cell anemia in a humanized sickle mouse model: critical determinants for successful correction. [2021]

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

Combination of lentiviral and genome editing technologies for the treatment of sickle cell disease. [2023]

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

An Optimized Lentiviral Vector Efficiently Corrects the Human Sickle Cell Disease Phenotype. [2020]

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

Development of β-globin gene correction in human hematopoietic stem cells as a potential durable treatment for sickle cell disease. [2022]

7. Italy pubmed.ncbi.nlm.nih.gov

Safety and efficacy of plerixafor dose escalation for the mobilization of CD34+ hematopoietic progenitor cells in patients with sickle cell disease: interim results. [2021]

8. Italy pubmed.ncbi.nlm.nih.gov

Plerixafor enables safe, rapid, efficient mobilization of hematopoietic stem cells in sickle cell disease patients after exchange transfusion. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Novel HDAd/EBV Reprogramming Vector and Highly Efficient Ad/CRISPR-Cas Sickle Cell Disease Gene Correction. [2018]

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

β-globin gene transfer to human bone marrow for sickle cell disease. [2021]