Transplantation of Clustered Regularly Interspaced Short Palindromic Repeats Modified Hematopoietic Progenitor Stem Cells (CRISPR_SCD001) in Patients With Severe Sickle Cell Disease

Transplantation of CRISPRCas9 Corrected Hematopoietic Stem Cells (CRISPR_SCD001) in Patients With Severe Sickle Cell Disease

This is an open label, non-randomized, 2-center, phase 1/2 trial of a single infusion of sickle allele modified cluster of differentiation (CD34+) hematopoietic stem progenitor cells (HSPCs) in subjects with in subjects ≥12 years old to 35 years old severe Sickle Cell Disease (SCD). The study will evaluate the hematopoietic stem cell transplantation (HSCT) using CRISPR/Cas9 edited red blood cells (known as CRISPR_SCD001 Drug Product).

Study Overview

• Status: Recruiting
• Conditions: Sickle Cell Disease
• Intervention / Treatment: Drug: CRISPR_SCD001

Detailed Description

This is an open label, non-randomized, 2-center, phase 1/2 trial of a single infusion of sickle allele modified CD34+ HSPCs in subjects with severe SCD. The primary endpoint of the trial will determine the safety of CRISPR_SCD001 through a 3+3 design with staggered enrollment and a pause in enrollment for safety review after each of the first 3 patients has had drug product infused. After safety is assessed in the 3rd patient, enrollment of the next 3 patients will not be staggered. The first six subjects will be adults. If CRISPR_SCD001 is determined to be safe in the first six subjects, the trial will continue to enroll 3 adolescents 12 - 18 years of age to evaluate the safety in younger patients. The younger age cohort also will follow staggered enrollment.

• Study Type: Interventional
• Enrollment (Estimated): 9
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Mark Walters, MD; Phone Number: (510) 428-3374; Email: Mark.Walters@ucsf.edu
• Study Contact Backup: Name: Christina Chun, MPH; Phone Number: (415) 502-2558; Email: Christina.Chun@ucsf.edu

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • Recruiting
      • University of California, Los Angeles
      • Contact: Augustine Fernandes, PhD; Email: afernandes@mednet.ucla.edu
      • Contact: Vladimir Kustanovich, PhD; Email: VKustanovich@mednet.ucla.edu
      • Principal Investigator: Gary J Schiller, MD
    • Oakland, California, United States, 94609
      • Recruiting
      • UCSF Benioff Children's Hospital
      • Principal Investigator: Mark Walters, MD
      • Contact: Marci Moriarty, RN BSN; Phone Number: 5396 (510) 428-3885; Email: marci.moriarty@ucsf.edu
      • Contact: Cyrus Bascon; Phone Number: 6953 (510) 428-3885; Email: cyrus.bascon@ucsf.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 35 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male or female 12.00 - 34.99 years of age (at time of consent) who have one or more of the following:

   1. 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); ACS is defined as a new radiodensity on chest imaging accompanied by fever and/or respiratory symptoms, treated in the hospital with supplemental oxygen at a minimum.
   2. History of at least 4 severe vaso-occlusive pain events in the 2-year period preceding enrollment despite the institution of supportive care measures (i.e. a pain management plan and/or treatment with hydroxyurea); painful episodes related to or any sickle-related acute event are acceptable; a severe painful vaso-occlusive event is defined as receiving analgesic treatment (opioid or other analgesic via parenteral (PN) route) for longer than 24 -hours in a hospital or emergency room (ER) observation unit visit or at least 2 visits in a day unit or ER over 72 hours with both visits requiring parenteral analgesics.
   3. 2 or more episodes of splenic sequestration, defined as an acute decrease in hemoglobin by at least 2 g/dL accompanied by splenomegaly in the 2 years before enrollment.
   4. Recurrent priapism (episodes lasting at least 4 hours at least twice in the last 12 months or 3 times in the last 24 months before enrollment) recalcitrant to medical treatment
   5. Any episode of hepatic sequestration defined as right upper quadrant pain, hepatomegaly, and rapidly decreasing hemoglobin level with hepatic dysfunction within the 2 years before enrollment.
   6. Leg ulcer recalcitrant to treatment within 2 years prior to enrollment.

2. Participants must have adequate physical function as measured by all of the following:

   1. Karnofsky performance score ≥60.
   2. Cardiac function: Left ventricular ejection fraction (LVEF) >40%; or LV shortening fraction > 26% by cardiac echocardiogram or by (multiple-gated acquisition) MUGA scan.
   3. Pulmonary function: Pulse oximetry with a baseline O2 saturation of ≥85% and diffusion capacity of lung for carbon monoxide(DLCO) > 40% (corrected for hemoglobin).
   4. Renal function: Serum creatinine ≤ 1.5 x upper limit of normal for age and estimated or measured creatinine clearance ≥ 70 mL/min/1.73 m2.
   5. Hepatic function:

   i. Serum conjugated (direct) bilirubin < 2x upper limit of normal for age as per local laboratory. Participants with hyperbilirubinemia as the result of hyperhemolysis, or a severe drop in hemoglobin post blood transfusion, are not excluded.

   ii. Alanine aminotransferase (ALT) and aspartate aminotransferase (AS < 5 times upper limit of normal as per local laboratory.

   Participants who have liver iron concentration (LIC) on liver MRI of ≥12 mg Fe/g liver dry weight should also have MR elastography (MRE) or Ultrasound elastography obtained. If severe fibrosis is present, no liver biopsy will be performed and participant is excluded. Children with LIC >12 and negative elastography imaging are eligible if a clinically indicated liver biopsy shows no significant fibrosis.

3. Baseline prothrombin time or partial thromboplastin time <1.5 ULN except if receiving a prophylactic anticoagulant which causes an elevated prothrombin or partial thromboplastin time.
4. 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.

Exclusion Criteria:

1. Participants with uncontrolled bacterial, viral or fungal infection in the 6 weeks before enrollment (currently taking medication with evidence of progression of clinical symptoms or radiologic findings).
2. Participants with evidence of HIV infection or seropositivity for HIV or active hepatitis B or C.
3. Participants who have received a Hematopoietic Cell Transplant (HCT)
4. Participants who have received a solid organ transplant.
5. 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.
6. Females who are pregnant or breast feeding.
7. Females of child bearing potential (to include all female participants > 10 years of age, unless postmenopausal for a minimum of 1 year before the time of consent or surgically sterilized) who do not agree to practice two (2) effective methods of contraception at the same time, or who do not agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject, from the time of signing of informed consent through 12 months post-stem cell infusion.
8. Males (even if surgically sterilized) who do not agree to practice effective barrier contraception, or who do not agree to practice true abstinence from the time of signing informed consent through 12 months post-stem cell infusion.
9. Participants who have had a stroke OR who are receiving red blood cell (RBC) transfusions to prevent primary stroke or silent cerebral infarction.
10. Patients who have a suitable human leukocyte antigen identical (HLA-ID) sibling donor willing and able to donate bone marrow.
11. Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data.
12. Any non-homozygous sickle hemoglobin (HbSS) genotype of SCD

13. Either or both of the following findings on screening bone marrow aspirate/biopsy:

    1. diagnosis of myelodysplastic syndrome (MDS) based on morphology and/or cytogenetics (based on WHO definitions) OR
    2. any evidence of a pathogenic clonal variant in any candidate gene detected by a standard, licensed next-generation sequencing clinical assay for gene mutations associated with hematological malignancies.
14. The participant has an identified pathogenic mutation associated with myeloid malignancy as identified by RHP or a variant of unknown significance (VUS) judged to be pathogenic for myeloid malignancy as determined by one or more members of the adjudication panel.

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: CRISPR_SCD001 Drug Product; 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.	Drug: CRISPR_SCD001; CRISPR_SCD001 is administered by IV infusion following myeloablative conditioning with busulfan.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	The adverse event rate will be summarized using descriptive statistics, together with 95% confidence intervals where appropriate. No formal statistical hypothesis testing will be performed. Adverse events defined: failure of engraftment, malignant clonal expansion related to genomic editing or death.	24 months post-transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in the annualized vaso-occlusive pain event (VOE) rates.	Change in the annualized vast-occlusive pain event (VOE) rates comparing the 24 months before with 24 months after the infusion of drug product.	24 months pre-transplant to 24 months post-transplant
Graft rejection defined as having an absolute neutrophil count (ANC) < 500 at 42 days post-infusion	A delay in platelet and/or neutrophil engraftment will be captured.	42 days post-transplant
Time to neutrophil recovery defined as the first of 3 measurements on different days when the patient has an absolute neutrophil count (ANC) of ≥500/µL after transplant.	Neutrophil recovery as part of the overall hematological recovery.	24 months post-transplant
Time to platelet recovery is defined as the first day of a minimum of 3 measurements on different days that the patient has achieved a platelet count > 50,000/µL AND did not receive a platelet transfusion in the previous 7 days.	Platelet recovery as part of the overall hematological recovery.	baseline, through 24 months post-transplant
Rate of improvement in Hemoglobin S (HbS) fraction as measured by hemoglobin electrophoresis, as percent of total.	Hemolysis markers.	baseline, through 24 months post-transplant
Rate of normalization in hemoglobin (hgb) level as measured by clinical hematology (laboratory) test.	Hemolysis markers.	baseline, through 24 months post-transplant
Rate of normalization of lactate dehydrogenase (LDH), reticulocyte count, and haptoglobin, as measured by clinical hematology and serum chemistry (laboratory) tests.	Hemolysis markers.	baseline, through 24 months post-transplant
Frequency of hepatic veno-occlusive disease (VOD) as measured by Seattle or Baltimore Criteria for VOD Diagnosis.	Hematologic and non-hematologic toxicities of autologous transplantation with CRISPR-Cas9 sickle-corrected HSPCs.	24 months post-transplant
Frequency of hepatic idiopathic pneumonia syndrome (IPS) as measured by the Idiopathic pneumonia syndrome (IPS) criteria.	Hematologic and non-hematologic toxicities of autologous transplantation with CRISPR-Cas9 sickle-corrected HSPCs.	24 months post-transplant
Frequency of central nervous system (CNS) toxicity (reversible posterior leukoencephalopathy syndrome [RPLS] or posterior reversible encephalopathy syndrome [PRES], hemorrhage, and seizures).	Hematologic and non-hematologic toxicities of autologous transplantation with CRISPR-Cas9 sickle-corrected HSPCs.	24 months post-transplant
Frequency of cytomegalovirus (CMV) infection, invasive fungal infection, and any other serious viral or bacterial infection	Hematologic and non-hematologic toxicities of autologous transplantation with CRISPR-Cas9 sickle-corrected HSPCs.	24 months post-transplant
Frequency of sickle gene-editing (correction and insertion/deletion) and off-target site-1 editing in marrow and peripheral blood mononuclear cells.	Stability of gene-editing in hematopoietic cells by genotyping studies.	3 months, 1 and 2 years post-transplant

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of sickle-related events other than severe VOE and end organ function.	Rate of sickle-related complications after infusion	24 months post-infusion
Patient-reported quality of life (pain and fatigue domains) as measured by the use of Patient Reported Outcome Measurement Information System (PROMIS) modules.	Change in quality of life score at baseline (prior to the initiation of hydroxyurea), 1 year and 2 years post-stem cell infusion accessed using Patient Reported Outcome Measurement Information System (PROMIS) modules. The PROMIS modules rate the following areas: Physical Function and Sleep Quality on a scale of 1 (not good) to 5 (good).; Anxiety, Depression, Fatigue, Pain Interference and the Ability to Participate in Social Roles and Activities on a scale of 1 (never) to 5 (always).; Pain Intensity on a scale from 0 (no pain) to 10 (worst pain imaginable).	baseline, and 1 and 2 years post-transplant
Change from baseline in cardiac-pulmonary function via pulmonary function tests		Through 1 and 2 years post-transplant
Change from baseline in cardiac-pulmonary function via echocardiogram (tricuspid regurgitant jet velocity [TRJV], LVEF).		Through 1 and 2 years post-transplant
Change from baseline in meters walked during 6-minute walk test (6MWD)		Through 1 and 2 years post-transplant
Event-free survival defined as survival without clinical and hematological evidence of the underlying Sickle Cell Disease (SCD)		1 and 2 years post-transplant

Collaborators and Investigators

• Sponsor: Mark Walters, MD
• Collaborators: University of California, Berkeley; University of California, Los Angeles
• Investigators: Principal Investigator: Mark Walters, MD, UCSF Benioff Children's Hospital Oakland

Study record dates

Study Major Dates

• Study Start (Actual): August 22, 2025
• Primary Completion (Estimated): March 1, 2030
• Study Completion (Estimated): March 1, 2030

Study Registration Dates

• First Submitted: February 17, 2021
• First Submitted That Met QC Criteria: February 24, 2021
• First Posted (Actual): March 1, 2021

Study Record Updates

• Last Update Posted (Actual): April 16, 2026
• Last Update Submitted That Met QC Criteria: April 13, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• 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
• Other Study ID Numbers: 21-33287

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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