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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new gene therapy for individuals with severe sickle cell disease to determine its safety and potential effectiveness. The treatment involves a special technique to modify blood stem cells from the patient's own body, specifically using the βAS3-FB vector transduced peripheral blood CD34+ cells. Suitable candidates have sickle cell disease, have not responded well to standard medication like hydroxyurea, and have experienced serious complications such as repeated pain crises or lung issues. This trial provides an opportunity to explore an innovative treatment option for those facing significant challenges with their condition. As a Phase 1, Phase 2 trial, it focuses on understanding the treatment's function in people and measuring its effectiveness in an initial, smaller group.

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.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that a new treatment using modified stem cells is undergoing safety testing in people with sickle cell disease. In a study with four patients who received this treatment, it was generally well-tolerated. No serious side effects were directly linked to the therapy, though some mild to moderate side effects occurred, which is common with stem cell transplants.

As this is an early-stage trial, the main goal is to ensure the treatment's safety and determine the correct dosage. Being in this phase indicates that earlier safety tests have shown enough promise to continue, including studies conducted in labs and initial trials with people. If this type of therapy is already approved for another condition, it often has a safety record that supports further testing for new uses. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for sickle cell disease?

Unlike the standard treatments for sickle cell disease, which often involve blood transfusions and medications like hydroxyurea to manage symptoms, the stem cell gene therapy being studied offers a potentially curative approach. This therapy uses a βAS3-FB vector to modify a patient's own stem cells, effectively correcting the genetic defect that causes sickle cell disease. Researchers are excited because this method targets the root cause of the disease rather than just alleviating symptoms, offering hope for a long-term solution.

What evidence suggests that this treatment might be an effective treatment for sickle cell disease?

Research shows that a new treatment using modified stem cells may help people with sickle cell disease. In studies, patients who received these specially altered stem cells experienced improvements in their condition. This trial will provide all participants with the intervention of βAS3-FB vector transduced peripheral blood CD34+ cells. This approach addresses the genetic issue causing sickle cell disease by using the patient's own stem cells. Early results suggest this method can help produce normal hemoglobin, potentially reducing the sickling of red blood cells. Although more research is needed, these initial findings offer hope for those with severe sickle cell disease. ^{1 2 5 6 7}

Who Is on the Research Team?

Gary Schiller, MD

Principal Investigator

University of California, Los Angeles

Donald Kohn, MD

Principal Investigator

University of California, Los Angeles

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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]

Citations

1. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2666636725004178

Clinical Outcomes of Lenti/G-βAS3-FB Lentiviral Vector ... Here, we report the clinical outcomes of four patients who underwent gene-modified autologous stem cell transplantation using the Lenti/G-βAS3-FB vector. Five ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT02247843

Study Details | NCT02247843 | Stem Cell Gene Therapy ... This Phase I clinical trial will assess the safety and initial evidence for efficacy of an autologous transplant of lentiviral vector modified peripheral blood ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6276308/

Pre-clinical Development of a Lentiviral Vector Expressing ... This study enables a phase I/II clinical trial aimed at correcting the SCD phenotype in juvenile patients by transplantation of autologous hematopoietic stem ...

4. journals.sagepub.com journals.sagepub.com/doi/full/10.1089/hum.2018.061

Gene Therapy for Sickle Cell Disease: A Lentiviral Vector ... The goal of this project was to compare the vectors head-to-head and analyze transduction efficiency in primary CD34+ cells, as well as β-globin expression in ...

5. scge.mcw.edu scge.mcw.edu/platform/data/clinicalTrials/report/NCT02247843

Stem Cell Gene Therapy for Sickle Cell Disease This Phase I clinical trial will assess the safety and initial evidence for efficacy of an autologous transplant of lentiviral vector modified ...

6. astctjournal.org astctjournal.org/article/S2666-6367(25)00417-8/fulltext

Clinical Outcomes of Lenti/G-βAS3-FB Lentiviral Vector ... Here, we report the clinical outcomes of four patients who underwent gene-modified autologous stem cell transplantation using the Lenti/G-βAS3-FB vector. Five ...

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1465324917306011

Preclinical studies for a phase 1 clinical trial of autologous ... Data are shown to evaluate and establish the feasibility of isolating, transducing with the Lenti/βAS3-FB vector and cryopreserving CD34+ cells from human bone ...