Gene Editing (CRISPR) for Sickle Cell Disease

Recruiting in Palo Alto (17 mi)

+2 other locations

Overseen by Mark Walters, MD

Age: < 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Mark Walters, MD

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

No Placebo Group

Approved in 1 Jurisdiction

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.

Trial 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 (Gene Editing)

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.

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+

Richard Lyons

University of California, Berkeley

Chief Executive Officer since 2023

PhD in Biochemistry from the University of California, Berkeley

Dr. Benjamin Hermalin

University of California, Berkeley

Chief Medical Officer since 2023

MD from Stanford University

University of California, Los Angeles

Collaborator

Trials

1,594

Recruited

10,430,000+

Dr. Thomas Rando

University of California, Los Angeles

Chief Medical Officer since 2023

MD from UCLA

Amir Naiberg

University of California, Los Angeles

Chief Executive Officer since 2024

JD from UCLA

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 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]

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]