What side effects are associated with this type of intervention?

Gene therapy and gene editing for Sickle Cell Disease, such as CRISPR/Cas9, are promising but still investigational. Potential side effects include off-target genetic modifications, immune reactions, and long-term unknown risks. Hydroxyurea, a common treatment, can cause bone marrow suppression, leading to lower blood cell counts, and gastrointestinal issues. Regular blood transfusions, another standard treatment, carry risks of iron overload, alloimmunization, and transfusion reactions. Each treatment option requires careful consideration of benefits versus risks, and ongoing monitoring by healthcare providers.

What prior FDA approvals exist?

The FDA has approved several drugs for the treatment of Sickle Cell Disease, including hydroxyurea, which has been extensively studied and shown to reduce the frequency of painful crises and other complications. More recently, the FDA approved voxelotor and crizanlizumab in 2019, which target different mechanisms of the disease. Voxelotor works by increasing hemoglobin's affinity for oxygen, thereby reducing sickling, while crizanlizumab is a monoclonal antibody that reduces the frequency of vaso-occlusive crises by inhibiting P-selectin. These treatments, while not gene therapies, represent significant advancements in managing SCD. Gene editing approaches, such as the CRISPR/Cas9 edited CD34+ hematopoietic stem progenitor cells being studied, aim to correct the sickle allele and offer a potential curative option, building on the progress made by these earlier FDA-approved therapies.

What other types of research exist?

Promising alternatives to CRISPR/Cas9 gene editing for Sickle Cell Disease patients include: 1) Hydroxyurea, which is recommended as the first-line therapy due to its efficacy in reducing vaso-occlusive pain and improving survival. 2) Chronic transfusions, which can manage complications and prevent strokes. 3) Hematopoietic cell transplantation, which offers a potential cure by replacing diseased cells with healthy donor cells. 4) Other gene therapy approaches, such as those focusing on reactivating fetal hemoglobin or using different genome engineering techniques, are also in clinical trials and show potential.

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Gene Editing

Gene Editing (CRISPR) for Sickle Cell Disease

Phase 1 & 2

Waitlist Available

Research Sponsored by Mark Walters, MD

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Karnofsky performance score ≥60.

History of two or more episodes of acute chest syndrome (ACS) in the 2-year period preceding enrollment despite the institution of supportive care measures (i.e. asthma therapy and/or hydroxyurea);

Must not have

Females who are pregnant or breast feeding.

Participants with evidence of HIV infection or seropositivity for HIV or active hepatitis B or C.

Timeline

Screening 3 weeks

Treatment Varies

Follow Up baseline, and 1 and 2 years post-transplant

Awards & highlights

Summary

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.

Who is the study for?

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.

What is being tested?

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.

What are the potential side effects?

Potential side effects are not explicitly listed but may include typical risks associated with stem cell transplantation such as immune reactions, infection risk increase due to immunosuppression during the procedure and potential off-target genetic effects.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I can care for myself but may need occasional help.

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I've had two or more acute chest syndrome episodes in the last 2 years despite treatment.

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I've had 4 or more severe pain crises due to sickle cell in the last 2 years despite treatment.

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My lung function tests show my oxygen levels and breathing capacity are within safe limits.

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My heart's pumping ability is within a healthy range.

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I am between 12 and 34 years old.

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My kidney function tests are within normal limits.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I am not pregnant or breastfeeding.

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

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My sickle cell disease is not the HbSS type.

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I have had a stroke or I get blood transfusions to prevent strokes.

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I have a sibling donor who is a perfect HLA match.

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I haven't had an uncontrolled infection in the last 6 weeks.

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I have received a stem cell transplant.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ baseline, and 1 and 2 years post-transplant

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~baseline, and 1 and 2 years post-transplant

This trial's timeline: 3 weeks for screening, Varies for treatment, and baseline, and 1 and 2 years post-transplant for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Incidence of adverse events and grade 3 or higher serious adverse events, using the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE)

Secondary study objectives

Change in the annualized vaso-occlusive pain event (VOE) rates.

Frequency of central nervous system (CNS) toxicity (reversible posterior leukoencephalopathy syndrome [RPLS] or posterior reversible encephalopathy syndrome [PRES], hemorrhage, and seizures).

Frequency of cytomegalovirus (CMV) infection, invasive fungal infection, and any other serious viral or bacterial infection

+9 more

Other study objectives

Patient-reported quality of life (pain and fatigue domains) as measured by the use of Patient Reported Outcome Measurement Information System (PROMIS) modules.

Rate of sickle-related events other than severe VOE and end organ function.

Trial Design

1Treatment groups

Experimental Treatment

Group I: CRISPR_SCD001 Drug ProductExperimental Treatment1 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.

0 / 14Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

The most common treatments for Sickle Cell Disease (SCD) include hydroxyurea, blood transfusions, and gene therapy. Hydroxyurea works by increasing fetal hemoglobin (Hb F) levels, which reduces the sickling of red blood cells and decreases vaso-occlusive events. Blood transfusions lower the proportion of sickle hemoglobin (Hb S) in the blood, helping to prevent complications such as pain crises and stroke. Gene therapy, including CRISPR/Cas9 gene editing, aims to correct the sickle cell mutation in hematopoietic stem cells, potentially offering a long-term cure by enabling the production of normal hemoglobin. These treatments are vital for SCD patients as they address the root causes of the disease, improving quality of life and reducing the risk of severe complications.