Gene Editing (CRISPR) for Sickle Cell Disease

Recruiting at 2 trial locations

Overseen By Christina Chun, MPH

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Mark Walters, MD

Disqualifiers: HIV, Hepatitis B/C, Organ transplant, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 25

Duration: 1 day

9 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a one-time treatment for patients with severe Sickle Cell Disease. The treatment aims to correct the genetic defect causing their disease, allowing their bodies to produce healthy red blood cells. The study will initially focus on ensuring the treatment is safe in older patients before expanding to younger ones.

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 participants should not have uncontrolled infections and should not be on certain treatments like red blood cell transfusions to prevent strokes. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the treatment CRISPR_SCD001 for Sickle Cell Disease?

Research shows that using CRISPR to edit specific genes in blood stem cells can increase the production of a type of hemoglobin that doesn't cause sickle cell disease symptoms. This approach has been successful in correcting the sickle cell mutation in lab settings, leading to the production of normal hemoglobin and reducing disease symptoms. ^{1 2 3 4 5}

Is CRISPR gene editing for sickle cell disease safe for humans?

Research shows that CRISPR gene editing for sickle cell disease has been tested in preclinical studies and has not shown evidence of causing abnormal blood cell development, cancer, or other harmful effects in animal models. These findings support the safety of this approach for further clinical trials in humans. ^{2 6 7 8 9}

How is the treatment CRISPR_SCD001 different from other treatments for sickle cell disease?

CRISPR_SCD001 is unique because it uses CRISPR gene-editing technology to modify the patient's own stem cells, correcting the genetic mutation that causes sickle cell disease. This approach aims to restore normal hemoglobin production and reduce sickling of red blood cells, offering a potential cure rather than just managing symptoms. ^{1 4 5 8 10}

Research Team

Mark Walters, MD

Principal Investigator

UCSF Benioff Children's Hospital Oakland

Eligibility Criteria

This trial is for individuals aged 12 to 35 with severe Sickle Cell Disease who've had multiple pain events or acute chest syndrome despite treatment, and have good kidney, liver, heart, and lung function. It's not for those with certain infections, pregnant or breastfeeding women, men unwilling to use contraception, or anyone who has received a transplant.

Inclusion Criteria

Written informed consent or assent obtained from subject or subject's legal representative and ability for subject to comply with the requirements of the study.

I can care for myself but may need occasional help.

I am physically fit based on several health checks.

Exclusion Criteria

I am not pregnant or breastfeeding.

Participants who have participated in another clinical trial in which the participant received an investigational or off-label use of a drug or device within 3 months prior to enrollment.

I do not have HIV or active hepatitis B or C.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Single infusion of CRISPR_SCD001 Drug Product (autologous CD34+ cell-enriched population modified by CRISPR-Cas9)

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including hematologic and non-hematologic toxicities

24 months

Regular visits (in-person and virtual) over 24 months

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

Long-term

Treatment Details

Interventions

• CRISPR_SCD001

Trial Overview The study tests a one-time infusion of CRISPR_SCD001-modified stem cells in patients with severe Sickle Cell Disease. This gene-editing approach aims to correct the sickle cell allele in hematopoietic stem cells to alleviate disease symptoms.

Participant Groups

Group I: CRISPR_SCD001 Drug Product Experimental Treatment 1 Intervention

CRISPR_SCD001 Drug Product (autologous CD34+ cell-enriched population that contains cells modified by the CRISPR-Cas9 ribonucleoprotein) dose will be ≥3.0×106 CD34+ cells/kg recipient weight for each subject and the upper limit cell dose is 20 ×106 CD34+ cells/kg.

CRISPR_SCD001 is already approved in United States for the following indications:

Approved in United States as CRISPR_SCD001 for:

• Severe Sickle Cell Disease

Who Is Running the Clinical Trial?

Mark Walters, MD

Lead Sponsor

Trials

1

Recruited

9+

University of California, Berkeley

Collaborator

Trials

193

Recruited

716,000+

University of California, Los Angeles

Collaborator

Trials

1,594

Recruited

10,430,000+

Findings from Research

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]

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 comprehensive library of induced pluripotent stem cells (iPSCs) specific to sickle cell disease was created from diverse patients, which can help in studying the disease and developing personalized treatments.

CRISPR/Cas gene editing tools were successfully used to correct the sickle hemoglobin mutation, demonstrating potential for future cell- and gene-based therapies for sickle cell anemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Comprehensive, Ethnically Diverse Library of Sickle Cell Disease-Specific Induced Pluripotent Stem Cells. Park, S., Gianotti-Sommer, A., Molina-Estevez, FJ., et al.[2018]

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]

CRISPR technology shows promise for treating Sickle Cell Disease by targeting the beta globin gene, but the effectiveness of gene editing varies based on the specific location of the DNA cut and differences among patient samples.

The study reveals that even within the same patient, the efficiency of homology-directed repair (HDR) can differ significantly depending on where the beta globin gene is targeted, highlighting the need for tailored gene editing strategies to improve clinical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Precise and error-prone CRISPR-directed gene editing activity in human CD34+ cells varies widely among patient samples. Modarai, SR., Kanda, S., Bloh, 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]

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]

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]

Gene editing techniques, such as CRISPR-Cas and base editing, show promise in treating sickle cell disease (SCD) by reactivating fetal hemoglobin (HbF) production, which can compensate for the defective adult hemoglobin (HbA) and reduce sickling of red blood cells.

Clinical trials and preclinical studies indicate that these genome editing strategies are not only effective in increasing HbF levels but also demonstrate a favorable safety profile, although concerns about potential off-target effects remain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical genome editing to treat sickle cell disease-A brief update. Zarghamian, P., Klermund, J., Cathomen, T.[2023]

Using CRISPR/Cas9 technology, researchers successfully corrected the sickle mutation in hematopoietic stem and progenitor cells from patients with sickle cell disease, achieving a correction efficiency of about 24.5%.

The gene-edited cells produced significantly less sickle-shaped red blood cells and increased normal hemoglobin levels, demonstrating the potential for this approach to effectively treat sickle cell disease while minimizing off-target effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Highly efficient editing of the β-globin gene in patient-derived hematopoietic stem and progenitor cells to treat sickle cell disease. Park, SH., Lee, CM., Dever, DP., et al.[2020]

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

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

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

A Comprehensive, Ethnically Diverse Library of Sickle Cell Disease-Specific Induced Pluripotent Stem Cells. [2018]

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

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

5. England pubmed.ncbi.nlm.nih.gov

Precise and error-prone CRISPR-directed gene editing activity in human CD34+ cells varies widely among patient samples. [2021]

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. 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

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

9. Switzerland pubmed.ncbi.nlm.nih.gov

Clinical genome editing to treat sickle cell disease-A brief update. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Highly efficient editing of the β-globin gene in patient-derived hematopoietic stem and progenitor cells to treat sickle cell disease. [2020]