Gene Editing for Sickle Cell Disease

Recruiting in Palo Alto (17 mi)

Overseen by Akshay Sharma, MBBS, MSc

Age: 18 - 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: St. Jude Children's Research Hospital

Disqualifiers: HIV, Hepatitis B, Hepatitis C, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This study is being done to test the safety of a new treatment called gene editing in Sickle Cell Disease (SCD) patients and to see if a single dose of this genetically modified cellular product will increase the amount of a certain hemoglobin called fetal hemoglobin (HbF) and help reduce the symptoms of SCD. Primary Objective * To assess the safety of autologous infusion of clustered regularly interspaced palindromic repeats (CRISPR)/ CRISPR associated protein (Cas9)-edited CD34+ hematopoietic stem and progenitor cells (HSPCs) in patients with severe SCD. Secondary Objective * To assess the efficacy autologous infusion of CRISPR/Cas9 genome-edited CD34+ HSPCs into patients with severe SCD.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it mentions that patients who are receiving regular red blood cell transfusions for stroke prevention may need to continue them if they cannot be safely stopped after the gene therapy.

What data supports the effectiveness of the treatment Gene-modified CD34+ cells for Sickle Cell Disease?

Research shows that gene editing of CD34+ cells can correct the sickle cell mutation, leading to the production of normal hemoglobin and reducing sickle hemoglobin. Studies in mice and non-human primates demonstrate that these corrected cells can successfully engraft and maintain the gene edits over time, suggesting potential clinical benefits for patients with Sickle Cell Disease. ^{1 2 3 4 5}

Is gene editing for sickle cell disease generally safe in humans?

Preclinical studies show that gene editing of CD34+ cells for sickle cell disease appears safe, with no evidence of abnormal blood cell development or cancer risk in animal models. These findings support the safety of this approach for future clinical trials in humans. ^{3 4 6 7 8}

How is the treatment Gene-modified CD34+ cells unique for sickle cell disease?

This treatment uses advanced gene editing tools like CRISPR/Cas9 to correct the genetic mutation causing sickle cell disease directly in the patient's stem cells, allowing them to produce normal hemoglobin. Unlike traditional treatments that manage symptoms, this approach aims to address the root cause of the disease by repairing the DNA in blood-forming cells. ^{1 2 3 4 5}

Research Team

Akshay Sharma, MBBS, MSc

Principal Investigator

St. Jude Children's Research Hospital

Eligibility Criteria

This trial is for patients with severe Sickle Cell Disease. Participants must have a history of symptoms related to SCD and be eligible for stem cell transplantation. Specific criteria will determine who can join, but details are not provided here.

Inclusion Criteria

Patients should be willing to participate in an additional long-term follow-up study after completion of this trial

I am considered eligible for a stem cell transplant using my own cells.

I will use birth control from the start of treatment for at least 6 months after.

Exclusion Criteria

I have liver problems.

I haven't had any serious infections in the last month.

I have a history of serious bleeding problems.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Mobilization and Collection

Participants receive daily injections of plerixafor for 3-5 days to mobilize HSPCs, followed by apheresis to collect the cells

1 week

Daily visits for injections and apheresis

Gene Editing and Preparation

Collected HSPCs are genetically modified using CRISPR/Cas9 and prepared for infusion

2-3 weeks

Conditioning and Infusion

Participants receive Busulfan chemotherapy for 4 days, followed by infusion of the gene-edited cells

1 week

Inpatient stay for chemotherapy and infusion

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

Regular follow-up visits

Long-term Follow-up

Participants are followed for an additional 12 years to monitor long-term effects

12 years

Treatment Details

Interventions

• Gene-modified CD34+ cells (Gene Therapy)

Trial Overview The study tests the safety and effectiveness of gene editing on CD34+ cells in SCD patients. It aims to see if this treatment increases fetal hemoglobin levels and reduces disease symptoms using CRISPR/Cas9 technology.

Participant Groups

Group I: Autologous, genetically modified CD34+ HSPCs Treatment Experimental Treatment 3 Interventions

All eligible participants receive intervention as described in the Detailed Description with the following: plerixafor, busulfan, and autologous, gene-modified CD34+ cells

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

St. Jude Children's Research Hospital Memphis, TN

Who Is Running the Clinical Trial?

St. Jude Children's Research Hospital

Lead Sponsor

Trials

451

Patients Recruited

5,326,000+

Findings from Research

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Editing a γ-globin repressor binding site restores fetal hemoglobin synthesis and corrects the sickle cell disease phenotype. Weber, L., Frati, G., Felix, T., et al.[2022]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CRISPR/Cas9-Mediated Correction of the Sickle Mutation in Human CD34+ cells. Hoban, MD., Lumaquin, D., Kuo, CY., et al.[2022]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical evaluation for engraftment of CD34+ cells gene-edited at the sickle cell disease locus in xenograft mouse and non-human primate models. Uchida, N., Li, L., Nassehi, T., et al.[2022]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selection-free genome editing of the sickle mutation in human adult hematopoietic stem/progenitor cells. DeWitt, MA., Magis, W., Bray, NL., et al.[2021]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Seamless correction of the sickle cell disease mutation of the HBB gene in human induced pluripotent stem cells using TALENs. Sun, N., Zhao, H.[2022]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficient Delivery and Nuclear Uptake Is Not Sufficient to Detect Gene Editing in CD34+ Cells Directed by a Ribonucleoprotein Complex. Modarai, SR., Man, D., Bialk, P., et al.[2020]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene editing without ex vivo culture evades genotoxicity in human hematopoietic stem cells. Zeng, J., Nguyen, MA., Liu, P., et al.[2023]

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]

References

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

Editing a γ-globin repressor binding site restores fetal hemoglobin synthesis and corrects the sickle cell disease phenotype. [2022]

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

CRISPR/Cas9-Mediated Correction of the Sickle Mutation in Human CD34+ cells. [2022]

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

Preclinical evaluation for engraftment of CD34+ cells gene-edited at the sickle cell disease locus in xenograft mouse and non-human primate models. [2022]

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

Selection-free genome editing of the sickle mutation in human adult hematopoietic stem/progenitor cells. [2021]

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

Seamless correction of the sickle cell disease mutation of the HBB gene in human induced pluripotent stem cells using TALENs. [2022]

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

Efficient Delivery and Nuclear Uptake Is Not Sufficient to Detect Gene Editing in CD34+ Cells Directed by a Ribonucleoprotein Complex. [2020]

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

Gene editing without ex vivo culture evades genotoxicity in human hematopoietic stem cells. [2023]

8. 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]