Gene Editing For Sickle Cell Disease

St. Jude Autologous Genome Edited Stem Cells For Sickle Cell Disease-1

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.

Study Overview

• Status: Recruiting
• Conditions: Sickle Cell Disease
• Intervention / Treatment: Drug: Plerixafor; Drug: Busulfan; Biological: Gene-modified CD34+ cells; Drug: Motixafortide

Detailed Description

Participants will receive a daily subcutaneous (under the skin) dose of motixafortide for up to 3 consecutive days to mobilize their hematopoietic stem and progenitor cells (HSPCs) into peripheral blood. Participants who cannot tolerate motixafortide may receive a daily subcutaneous dose of plerixafor as an alternative for 3-5 consecutive days. The collection of HSPCs will be done via apheresis. The collected HSPCs will be sent to a lab to genetically modify them using CRISPR/Cas9.

In the lab, the researchers will take the stem cells and purify them. The stem cells will then be mixed with the CRISPR-Cas9 gRNA ribonucleoprotein (RNP) complex to change (edit) the genes in the cells and produce the new gene edited cellular product. This gene edited drug product will be frozen until ready for infusion.

Once the cellular product is ready, participants will be given Busulfan (a chemotherapy medicine) intravenously (IV) for 4 days. The thawed gene product will be given IV about 48 hours after the completion of the last dose of busulfan.

Participants will be followed for 3 years on this study. After the three years, participants will be followed for 12 more years on a long-term follow-up study.

• Study Type: Interventional
• Enrollment (Estimated): 25
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Akshay Sharma, MBBS, MSc; Phone Number: 888-226-4343; Email: referralinfo@stjude.org

Study Locations

• United States
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • Recruiting
      • St. Jude Children's Research Hospital
      • Contact: Akshay Sharma, MBBS, MSc; Phone Number: 888-226-4343; Email: referralinfo@stjude.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥18 years and ≤24.9 years.
• Patients with SCD (Hb SS, Hb SB0 and Hb SB+ genotype) who have experienced EITHER (a) 2 or more SCD-related vaso-occlusive events (acute pain events, acute chest syndrome, priapism and splenic sequestration) per year in the 2-year period before screening, OR (b) administration of regular red blood cell (RBC) transfusions (≥8 transfusions in the 12 months preceding enrollment) EXCEPT if the RBC transfusions are being administered for primary or secondary stroke prevention and, in the opinion of the treating hematologist, cannot be safely discontinued after infusion of the gene modified drug product.
• Failure, intolerance, or refusal of hydroxyurea therapy.
• Patients must be eligible for autologous stem cell transplant as per investigator's judgment.
• Females of childbearing potential (i.e., those who are post-menarchal with an intact uterus and at least 1 ovary, and those who are less than 1 year postmenopausal) must agree to use acceptable method(s) of contraception from start of mobilization through at least 6 months post-infusion.
• Males must agree to use effective contraception from start of mobilization through at least 6 months post-infusion.
• Patients should be willing to participate in an additional long-term follow-up study after completion of this trial.

Exclusion Criteria:

• Availability of an human leukocyte antigen (HLA)-matched sibling who is willing and able to donate an appropriate graft for hematopoietic cell transplantation (HCT).
• Karnofsky or Lansky performance score < 80.
• Pregnant, as confirmed by positive serum or urine pregnancy test within 14 days before enrollment (if female).
• Breastfeeding.
• Uncontrolled (undergoing appropriate treatment and with progression of clinical symptoms) or clinically significant bacterial, viral, or fungal infections within 1 month before enrollment.
• Patients with confirmed Hepatitis B or Hepatitis C infections.
• Patients with confirmed seropositivity or positive nucleic acid amplification test (NAAT) for human immunodeficiency virus (HIV) or human T-cell lymphotropic virus (HTLV).
• Patients with a history of stroke.
• Serum conjugated (direct) bilirubin > 2× the upper limit of normal for age, or serum alanine transaminase (ALT) > 3× the upper limit of normal for age as per the local laboratory. Participants with hyperbilirubinemia or elevated aspartate aminotransferase (AST) as the result of hyperhemolysis, or with a severe drop in hemoglobin post blood transfusion, are not excluded as long as these values downtrend and return to acceptable limits subsequently.
• Left ventricular shortening fraction < 25% or ejection fraction < 45% by echocardiogram.
• Estimated creatinine clearance less than 60 mL/min/1.73m^2.
• Diffusion capacity of carbon monoxide (DLCO) < 50% (adjusted for hemoglobin) OR baseline oxygen saturation < 85% in patients unable to perform pulmonary function tests.
• Prior HCT or gene therapy.
• Known hepatic cirrhosis, bridging hepatic fibrosis, or active hepatitis. Appropriate ultrasound or magnetic resonance (MR) imaging may be used to define the presence and degree of cirrhosis. Liver biopsy may be performed at the discretion of the attending physician or principal investigator if there are concerns regarding the presence of severe hepatic fibrosis or cirrhosis such that participation in this trial will not be in the patient's best interest.
• Active known malignancy, myelodysplasia, abnormal cytogenetics, or immunodeficiency.
• Patients with history of a significant bleeding disorder.
• Cerebrovascular procedure within 6 months, including pial synangiosis for moyamoya.
• Patients with history of untreated moyamoya disease or presence of moyamoya disease at screening that in the opinion of the investigator puts the subjects at the risk of bleeding.
• Evidence of a pathogenic clonal variant in any candidate gene detected by a standard, licensed next-generation sequencing clinical assay for gene mutations associated hematological malignancies.
• Patients with history of intolerance, contraindication, or known sensitivity to plerixafor or motixafortide or busulfan. Prior anaphylactic reaction with excipients of the proposed product.
• Patients with participation in another clinical study with an investigational drug/product within 30 days of screening or fewer than 5 half-lives of the investigational agent whichever is longer from screening.
• Patients with history of alloimmunization to RBC antigens and for whom the investigator anticipates that there will be insufficient RBC units available for the duration of the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Autologous, genetically modified CD34+ HSPCs Treatment; All eligible participants receive intervention as described in the Detailed Description with the following: motixafortide, plerixafor, busulfan, and autologous, gene-modified CD34+ cells	Drug: Plerixafor; Given Subcutaneous (under the skin); Other Names: Mozobil®; Drug: Busulfan; Given Intravenous (IV); Other Names: Busulfex; Myleran®; Biological: Gene-modified CD34+ cells; Given Intravenous (IV); Drug: Motixafortide; Given Subcutaneous (under the skin); Other Names: Aphexda

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of neutrophil engraftment by day +42 after infusion of the CRISPR/Cas9-edited CD34+ HSPCs.	Upon completion of the trial, summary statistics will be computed for the time to neutrophil engraftment.	Within 42 days of the cellular product infusion
Incidence of platelet engraftment by day +60 after infusion of the CRISPR/Cas9-edited CD34+ HSPCs.	Upon completion of the trial, summary statistics will be computed for the time to platelet engraftment.	Within 60 days of the cellular product infusion
Sustenance of multi-lineage engraftment and polyclonal hematopoiesis as measured by counts of different clones of myeloid cells, T cells, B cells, and NK cells at 1 year after infusion of the CRISPR/Cas9-edited CD34+ HSPCs.	Sustenance of multi-lineage engraftment will be described using descriptive statistics.	Within 1 year of the cellular product infusion
Frequency of off-target editing after infusion of the CRISPR/Cas9-edited CD34+ HSPCs.	Frequency of off-target editing will be described using descriptive statistics.	Within 3 years of the cellular product infusion
Occurrence of secondary graft failure, clonal hematopoiesis, MDS, or AML	Occurrence will be described using descriptive statistics.	Within 3 years of the cellular product infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Estimate the change in the annualized rate of SCD-related vaso-occlusive events (such as pain crises and acute chest syndrome events), starting at 3 months after the infusion of autologous CRISPR/Cas9-edited CD34+ HSPCs.	We will evaluate the change in the annualized rate of SCD-related vaso-occlusive events starting at 3 months after the infusion of autologous gene-edited CD34+ HSPCs relative to the annualized rate calculated during the 2-year period before study enrollment. The changes will be summarized using descriptive statistics and displayed graphically.	From 3 months post the cellular product infusion to 3 years post infusion
Compare the change from baseline in the total blood hemoglobin concentration.	The change from baseline (at the time of screening) in the total blood hemoglobin concentration will be calculated at various timepoints as described in the protocol. The changes will be summarized using descriptive statistics and displayed graphically.	From time of screening to 3 years post infusion
Compare the change from baseline in the fraction of red blood cells (RBCs) containing HbF.	The change from baseline (at the time of screening) in the fraction of RBCs containing HbF by immunostaining will be calculated at various timepoints as described in the protocol. The changes will be summarized using descriptive statistics and displayed graphically.	From time of screening to 3 years post infusion
Change in incidence of packed RBC transfusions.	The change from baseline (at the time of screening) in the incidence of packed RBC transfusions will be calculated at various timepoints as described in the protocol. The changes will be summarized using descriptive statistics and displayed graphically.	Within 1 year prior to infusion and within 3 months to 1 year post infusion

Collaborators and Investigators

• Sponsor: St. Jude Children's Research Hospital
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Akshay Sharma, MBBS, MSc, St. Jude Children's Research Hospital

Publications and helpful links

Helpful Links

• Clinical Trials Open at St. Jude
• St. Jude Children's Research Hospital

Study record dates

Study Major Dates

• Study Start (Actual): March 21, 2025
• Primary Completion (Estimated): December 1, 2029
• Study Completion (Estimated): December 1, 2032

Study Registration Dates

• First Submitted: June 14, 2024
• First Submitted That Met QC Criteria: July 11, 2024
• First Posted (Actual): July 17, 2024

Study Record Updates

• Last Update Posted (Actual): May 5, 2026
• Last Update Submitted That Met QC Criteria: April 29, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Gene Editing; Autologous; Apheresis; Busulfan; Plerixafor; Conditioning; CD34+ cells
• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Hematologic Diseases; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hemoglobinopathies; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hemic and Lymphatic Diseases; Anemia, Sickle Cell; Sulfur Compounds; Organic Chemicals; Hydrocarbons, Acyclic; Hydrocarbons; Alkanes; Alcohols; Butylene Glycols; Glycols; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Sulfonic Acids; Sulfur Acids; Busulfan; plerixafor
• Other Study ID Numbers: SAGES1; U01HL163983 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant de-identified datasets containing the variables analyzed in the published article will be made available (related to the study primary or secondary objectives contained in the publication). Supporting documents such as the protocol, statistical analyses plan, and informed consent are available through the CTG website for the specific study. Data used to generate the published article will be made available at the time of article publication. Investigators who seek access to individual level de-identified data will contact the computing team in the Department of Biostatistics (ClinTrialDataRequest@stjude.org) who will respond to the data request.
• IPD Sharing Time Frame: Data will be made available at the time of article publication.
• IPD Sharing Access Criteria: Data will be provided to researchers following a formal request with the following information: full name of requestor, affiliation, data set requested, and timing of when data is needed. As an informational point, the lead statistician and study principal investigator will be informed that primary results datasets have been requested.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No