Gene Editing for Sickle Cell Disease

Overseen By Akshay Sharma, MBBS, MSc

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: St. Jude Children's Research Hospital

Disqualifiers: HIV, Hepatitis B, Hepatitis C, others

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

Compensation: Varies

Number of Visits: Unknown

25 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety of a new gene editing treatment for people with severe Sickle Cell Disease (SCD). The treatment uses gene-modified CD34+ cells to increase levels of fetal hemoglobin, which can alleviate SCD symptoms such as pain and organ damage. It suits individuals with SCD who frequently experience painful events or require regular blood transfusions and have not found success with other treatments like hydroxyurea. As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the chance to be among the first to receive this innovative therapy.

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 prior data suggests that this gene editing treatment is safe for Sickle Cell Disease patients?

Earlier studies using CRISPR gene editing for sickle cell disease showed promising safety results. Research indicates that a single dose of the gene-modified cells was generally safe, with most participants experiencing no serious side effects. Some mild side effects occurred, but they were manageable and short-lived. This suggests the treatment could be safe for many patients. However, as this is an early-phase trial, the primary goal is to ensure safety. The results are encouraging so far, but further research is needed to confirm long-term safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about the gene-modified CD34+ cells treatment for sickle cell disease because it offers a revolutionary approach by using gene editing technology. Unlike current treatments that mainly focus on managing symptoms or providing blood transfusions, this treatment targets the root cause by correcting the genetic defect in the patient's own stem cells. This method has the potential to offer a long-term solution by effectively reducing or even eliminating the production of sickled red blood cells. Additionally, the use of autologous cells—meaning the patient's own cells—minimizes the risk of rejection, making it a promising and personalized treatment option.

What evidence suggests that gene editing might be an effective treatment for Sickle Cell Disease?

Research has shown that CRISPR-Cas9 gene editing could help treat sickle cell disease (SCD). This trial will use autologous, gene-modified CD34+ cells to potentially increase fetal hemoglobin (HbF), which might alleviate SCD symptoms. One study successfully edited these blood stem cells at a high rate, suggesting that a single treatment could reduce the need for ongoing care. While early results are promising, further research is necessary to confirm long-term benefits and safety. ^{1 3 4 5 6}

Who Is on the Research Team?

Akshay Sharma, MBBS, MSc

Principal Investigator

St. Jude Children's Research Hospital

Are You a Good Fit for This Trial?

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 heart problems.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Gene-modified CD34+ cells

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.

How Is the Trial Designed?

Group I: Autologous, genetically modified CD34+ HSPCs Treatment Experimental Treatment 4 Interventions

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

Who Is Running the Clinical Trial?

St. Jude Children's Research Hospital

Lead Sponsor

Trials

451

Recruited

5,326,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Published Research Related to This Trial

Targeted genome editing using CRISPR/Cas9 and TALENs can successfully correct the sickle cell mutation in the β-globin gene in hematopoietic stem cells, leading to the production of normal hemoglobin.

In laboratory tests, over 18% of CD34+ cells showed successful gene modification, indicating the potential for effective treatment of sickle cell disease in patients.

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]

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 gene-editing approach using electroporation achieved significant correction of the sickle cell mutation in hematopoietic stem cells, with about 30% correction at the DNA level and 80% at the protein level, demonstrating its potential efficacy for treating sickle cell disease.

The study showed that gene-edited CD34+ cells could successfully engraft and function in both mouse models and rhesus macaques for up to 12 months, indicating the long-term viability of this gene correction strategy for future clinical trials.

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]

The study demonstrates that using a ribonucleoprotein (RNP) complex with Cas9 and single-stranded DNA oligonucleotide can effectively edit the genes of hematopoietic stem/progenitor cells (HSPCs) from sickle cell disease (SCD) patients, leading to reduced sickle hemoglobin and increased normal hemoglobin production.

Ex vivo edited HSPCs maintained the genetic corrections for at least 16 weeks in immunocompromised mice, indicating the potential for long-term therapeutic benefits in treating SCD and similar blood disorders.

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]

The study successfully corrected the sickle cell disease mutation in patient-derived human induced pluripotent stem cells (hiPSCs) using a precise genome editing tool called TALENs, which minimizes off-target effects.

This approach not only restores normal cell functions but also preserves the pluripotency and normal genetic structure of the hiPSCs, marking a significant advancement towards developing effective cell and gene therapies for genetic disorders like sickle cell disease.

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]

Combining CRISPR-Cas9 editing of the BCL11A enhancers significantly enhances fetal hemoglobin (HbF) induction, which is crucial for treating β-hemoglobinopathies like sickle cell disease, as shown in patient-derived xenografts.

Editing hematopoietic stem and progenitor cells (HSPCs) without prior cytokine culture reduces the risk of unintended genetic damage while maintaining effective gene editing, suggesting a safer approach for potential in vivo therapies.

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]

Using CRISPR-Cas9 to edit the LRF-binding site in hematopoietic stem/progenitor cells can increase fetal γ-globin production, which helps correct the sickling of red blood cells in sickle cell disease (SCD).

The study demonstrated high editing efficiency in repopulating stem cells, suggesting that targeting the LRF-binding site could be a promising approach for developing genome-editing therapies for SCD.

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]

CD34+ cells are important for gene editing strategies, but the methods for delivering gene editing tools, like CRISPR/Cas9, need improvement to ensure effective nuclear uptake and gene editing activity.

In this study, while the Neon Transfection System showed accumulation of CRISPR/Cas9 at the cell membrane, only nucleofection allowed the ribonucleoproteins to enter the nucleus; however, neither method successfully edited the gene, highlighting the need for better protocols in clinical applications for sickle cell disease.

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9180595/

Hematopoietic Stem Cell Gene-Addition/Editing Therapy in ... Autologous hematopoietic stem cell (HSC)-targeted gene therapy provides a one-time cure for various genetic diseases including sickle cell disease (SCD) and β- ...

2. nejm.org nejm.org/doi/full/10.1056/NEJMoa2031054

CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β ... We assessed the frequency of gene editing associated with CTX001 in CD34+ HSPCs obtained from 10 healthy donors. High frequencies of allelic ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT06506461?term=CRISPR&cond=Sickle%20Cell%20Disease&viewType=Table&rank=2

NCT06506461 | Gene Editing For Sickle Cell Disease 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 ...

4. ash.confex.com ash.confex.com/ash/2024/webprogram/Paper204888.html

Initial Results from the BEACON Clinical Study: A Phase ... BEAM-101 is an investigational cell therapy comprised of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) that are base edited ...

5. frontiersin.org frontiersin.org/journals/hematology/articles/10.3389/frhem.2024.1468952/full

Recent advancements in gene therapy for sickle cell ... Data from these clinical studies suggest that younger patients have better outcome from Lenti-globin gene therapy and a minimum transduction threshold of CD34+ ...

6. investors.beamtx.com investors.beamtx.com/news-releases/news-release-details/beam-therapeutics-present-updated-data-beacon-phase-12-trial

Press Release BEAM-101 is an investigational genetically modified cell therapy for the treatment of sickle cell disease (SCD). The one-time therapy ...