Stem Cell Gene Therapy for Cystinosis

NCT03897361 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: 018631
• Study Type: interventional
• Target: 7
• Locations: 1 country
• Sites: 1

Brief Summary

This study is a Phase 1/2 clinical trial that will assess the safety and efficacy of enriched gene-corrected hematopoietic stem cells isolated from patients affected with cystinosis. (Investigational Product: CTNS-RD-04, including product manufactured with and without the transduction enhancer LentiBOOST \[CTNS-RD-04-LB\])

Conditions

Lysosomal Storage Diseases; Cystinosis

Keywords

Cystinosis; Lysosomal Storage Disorders; LSD

Outcome Measures

Primary Outcomes (13)

• Safety and Tolerability: Total Number of Adverse Events (AEs) Per Participant (Pre- and Post-dose to End of Study)

  The total count of all adverse events (AEs) recorded for each dosed participant reported at any scheduled study visit starting with the first pre-dose safety visit (i.e., the first visit after informed consent and before the first administration of study drug) and continuing through the end of the treatment period. Events were coded using MedDRA and graded according to NCI CTCAE criteria. The outcome is the total count of AEs per participant.

  From the first pre-dose safety visit to the end of the treatment period (e.g., 24 months post-dose) or the participant's last safety-assessment visit, whichever occurs later.

• Safety and Tolerability: Aggregate Number of Adverse Events (AEs) by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Severity (Pre-dose and Post-dose to End of Study)

  The total aggregate count of all graded adverse events (AEs) recorded for all dosed participants reported at any scheduled study visit starting with the first pre-dose safety visit (i.e., the first visit after informed consent and before the first administration of study drug) and continuing through the end of the treatment period. Events were coded using MedDRA v24.0 and graded according to NCI CTCAE version 4.03. The outcome is the total count of AEs per grade (Mild, Moderate, Severe, Life Threatening, Death).

  From the first pre-dose safety visit to the end of the treatment period (e.g., 24 months post-dose) or the participant's last safety-assessment visit, whichever occurs later.

• Safety and Tolerability: Aggregate Number of Adverse Events (AEs) by Relationship to Study Treatment (Pre-dose and Post-dose to End of Study)

  The total aggregate count of all adverse events (AEs) categorized by relationship to the study treatment recorded for all dosed participants reported at any scheduled study visit starting with the first pre-dose safety visit (i.e., the first visit after informed consent and before the first administration of study drug) and continuing through the end of the treatment period. Relationship to the study treatment was determined using the standard categories defined in the protocol: Related (probably or possibly related); Unrelated (not related, unlikely related). Each AE was coded with MedDRA v24.0. The outcome reported is the study-wide total count of AEs in each relationship category.

  From the first pre-dose safety visit to the end of the treatment period (e.g., 24 months post-dose) or the participant's last safety-assessment visit, whichever occurs later.

• Safety and Tolerability: White Blood Cell Count at Baseline, 12-month, and 24-month Post-infusion

  Clinical laboratory values for white blood cell (WBC) count at baseline, approximately 12 months and approximately 24 months post-infusion study visits. Results are summarized as mean (SD) across dosed participants with evaluable data at each timepoint.

  Baseline, approximately 12 months post-infusion, and approximately 24 months post-infusion.

• Safety and Tolerability: Absolute Monocyte Count at Baseline, 12-month, and 24-month Post-infusion

  Clinical laboratory values for absolute monocyte count at baseline, approximately 12 months and approximately 24 months post-infusion study visits. Results are summarized as mean (SD) across dosed participants with evaluable data at each timepoint.

  Baseline, approximately 12 months post-infusion, and approximately 24 months post-infusion.

• Safety and Tolerability: Platelet Count at Baseline, 12 Month and 24 Month Post-infusion

  Clinical laboratory values for platelet count at baseline, approximately 12 months and approximately 24 months post-infusion study visits. Results are summarized as mean (SD) across dosed participants with evaluable data at each timepoint.

  Baseline, approximately 12 months post-infusion, and approximately 24 months post-infusion.

• Safety and Tolerability: Systolic and Diastolic Blood Pressure at Baseline, 12-month, and 24-month Post-infusion Study Visits

  Systolic and diastolic blood pressure at baseline, approximately 12 months and approximately 24 months post-infusion study visits. Measurements were taken with subjects positioned supine, seated, or semi-Fowler's position. Results are summarized as mean (SD) across dosed participants with evaluable data at each timepoint.

  Baseline, approximately 12 months post-infusion, and approximately 24 months post-infusion.

• Safety and Tolerability: Heart Rate at Baseline, 12-month, and 24-month Post-infusion Study Visits

  Heart rate at baseline, approximately 12 months and approximately 24 months post-infusion study visits. Measurements were taken with subjects positioned supine, seated, or semi-Fowler's position. Results are summarized as mean (SD) across dosed participants with evaluable data at each timepoint.

  Baseline, approximately 12 months post-infusion, and approximately 24 months post-infusion.

• Safety and Tolerability: Body Temperature at Baseline, 12-month, and 24-month Post-infusion Study Visits

  Body temperature at baseline, approximately 12 months, and approximately 24 months post-infusion study visits. Results are summarized as mean (SD) across dosed participants with evaluable data at each timepoint.

  Baseline, approximately 12 months post-infusion, and approximately 24 months post-infusion.

• Safety and Tolerability: Respiratory Rate at Baseline, 12-month, and 24-month Post-infusion Study Visits

  Respiratory rate at baseline, approximately 12 months and approximately 24 months post-infusion study visits. Measurements were taken with subjects positioned supine, seated, or semi-Fowler's position. Results are summarized as mean (SD) across dosed participants with evaluable data at each timepoint.

  Baseline, approximately 12 months post-infusion, and approximately 24 months post-infusion.

• Safety and Tolerability: Electrocardiogram (ECG) Ventricular Rates at Baseline, 12-month, and 24-month Post-infusion Study Visits

  Electrocardiogram (ECG) ventricular rate at baseline, approximately 12 months and approximately 24 months post-infusion study visits. ECG recordings were obtained using standard 12-lead resting ECGs. Results are summarized as mean (SD) across dosed participants with evaluable data at each timepoint.

  Baseline, approximately 12 months post-infusion, and approximately 24 months post-infusion.

• Safety and Tolerability: Electrocardiogram (ECG) Intervals Including PR Interval, QRS Interval, QT Interval and QTc Bazett at Baseline, 12 Month and 24 Month Post-infusion Study Visits

  Electrocardiogram (ECG) intervals including PR interval, QRS interval, QT interval and QTc Bazett at baseline, approximately 12 months and approximately 24 months post-infusion study visits. ECG recordings were obtained using standard 12-lead resting ECGs. Results are summarized as mean (SD) across dosed participants with evaluable data at each timepoint.

  Baseline, approximately 12 months post-infusion, and approximately 24 months post-infusion.

• Safety: Number of Dosed Participants Showing Evidence (Positive or Negative) of Genotoxicity as Determined by Polyclonal Expansion and Insertional Mutagenesis

  The number of dosed participants showing evidence (positive or negative) of polyclonal expansion and insertional mutagenesis as determined by vector integration site (VIS) analysis in whole blood collected at baseline and at approximately 1, 3, 6, 12, 18, and 24 months post-transplant. VIS analysis was performed using LTR-based PCR amplification and Illumina sequencing. Clonal abundance was monitored using the Sonic Abundance method.

  Up to 24 months post-transplant

Secondary Outcomes (5)

• Efficacy: Cystine Levels in Leukocytes and Granulocytes at Baseline, 12 Month and 24 Month Post-infusion Study Visits

  Baseline, approximately 12 months post-infusion, and approximately 24 months post-infusion.

• Efficacy: Clinical Laboratory Values of Estimated Glomerular Filtration Rate (eGFR) at Baseline, 12 Month and 24 Month Post-infusion Study Visits

  Baseline, approximately 12 months post-infusion, and approximately 24 months post-infusion.

• Efficacy: Clinical Laboratory Values of Thyroxine (T4) Endocrine Levels at Baseline, 12 Month and 24 Month Post-infusion Study Visits

  Baseline, approximately 12 months post-infusion, and approximately 24 months post-infusion.

• Efficacy: Clinical Laboratory Values Thyroid-stimulating Hormone (TSH) Endocrine Levels at Baseline, 12 Month and 24 Month Post-infusion Study Visits

  Baseline, approximately 12 months post-infusion, and approximately 24 months post-infusion.

• Transduction Efficiency: Vector Copy Number (VCN) in Peripheral Blood at 12 Month and 24 Month Post-infusion Study Visits

  Approximately 12 months post-infusion and approximately 24 months post-infusion.

Study Arms (1)

Gene Therapy with CTNS-RD-04 (including product manufactured with and without LentiBOOST)

EXPERIMENTAL

This is a single-arm, open-label study without randomization. Eligible subjects received CTNS-RD-04, an autologous CD34+ hematopoietic stem cell product transduced ex vivo with a lentiviral vector encoding CTNS. During the study, manufacturing incorporated a transduction enhancer (LentiBOOST) in later participants.

Genetic: CTNS-RD-04 (including CTNS-RD-04-LB manufactured with LentiBOOST)

Interventions

CTNS-RD-04 (including CTNS-RD-04-LB manufactured with LentiBOOST) GENETIC

Cryopreserved autologous CD34+ enriched hematopoietic stem/progenitor cells collected from mobilized peripheral blood and transduced ex vivo with a self-inactivating lentiviral vector (pCCL-CTNS or pCDY.EFS.CTNS.T260I) encoding the human CTNS complementary deoxyribonucleic acid (cDNA) sequence. In later participants, a transduction enhancer (LentiBOOST) was incorporated into the manufacturing process.

Gene Therapy with CTNS-RD-04 (including product manufactured with and without LentiBOOST)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• The following criteria must be met by all subjects considered for study participation.
• Cohorts 1 and 2: Male or female subject is ≥ 18 years of age.
• Cohort 3: Male or female subject is ≥ 14 years of age.
• Subject is diagnosed with cystinosis, i.e., early onset of Fanconi syndrome, and history of elevated white blood cell cystine level and/or history of or presence of cystine crystals in the eye.
• Subject has a Karnofsky Performance Status or age-dependent Lansky Performance of ≥ 60.
• If subject has had a kidney transplant, he or she must be at least one-year post kidney transplant status.
• Subject has adequate hematologic function:
• Absolute neutrophil count (ANC) ≥ 1.5 x 1000/mm\^3
• Platelet count ≥ 100 x 1000/mm\^3
• Hemoglobin ≥ 9.0 gm/dL
• Subject has an adequate hepatic function:
• Bilirubin ≤ 2.0 mg/ dL
• ALT ≤ 3 x institution's upper limit of normal (ULN) U/L
• Subject has an adequate renal function:
• a. Serum creatinine \<2x ULN mg/dL

You may not qualify if:

• Subject has an active, uncontrolled, acute bacterial, viral, or fungal infection during screening or within 30 days prior to starting the conditioning regimen.
• Subject has positive serology at screening for any of the following:
• Human Immunodeficiency Virus (HIV) 1-2
• Human T-cell Lymphotropic Virus (HTLV) - I/II
• Hepatitis B core and Hepatitis B PCR positive
• Hepatitis C Virus (HCV)
• Rapid Plasma Reagin (RPR)
• Chagas' Disease (T. curzi)
• QuantiferonTB
• Nucleic Acid Test (NAT) for HIV
• West Nile Virus (WNV)
• Subject has a known clinically significant immunodeficiency disorder.
• Subject is a female of childbearing potential that is nursing, planning a pregnancy or has a positive serum pregnancy test.
• Subject has received a prior marrow or stem cell transplantation or is planning to receive one within 90 days of study initiation.
• Subject has had an active bleeding disorder within 90 days prior to screening OR requires anticoagulation therapy prior to treatment with ex vivo gene therapy.

Sponsors & Collaborators

• University of California, San Diego: lead
• California Institute for Regenerative Medicine (CIRM): collaborator
• Cystinosis Research Foundation: collaborator

Study Sites (1)

University of California San Diego

La Jolla, California, 92093, United States

Location

Related Publications (4)

• Harrison F, Yeagy BA, Rocca CJ, Kohn DB, Salomon DR, Cherqui S. Hematopoietic stem cell gene therapy for the multisystemic lysosomal storage disorder cystinosis. Mol Ther. 2013 Feb;21(2):433-44. doi: 10.1038/mt.2012.214. Epub 2012 Oct 23.

  PMID: 23089735 BACKGROUND

• Naphade S, Sharma J, Gaide Chevronnay HP, Shook MA, Yeagy BA, Rocca CJ, Ur SN, Lau AJ, Courtoy PJ, Cherqui S. Brief reports: Lysosomal cross-correction by hematopoietic stem cell-derived macrophages via tunneling nanotubes. Stem Cells. 2015 Jan;33(1):301-9. doi: 10.1002/stem.1835.

  PMID: 25186209 BACKGROUND

• Afshari NA, Lee BJ, Borooah S, Nudleman E, Ahmed I, Sawyers A, Arias JM, Manalang N, Cherqui S. Comprehensive Ocular Characteristics in Cystinosis after Hematopoietic Stem-Cell Gene Therapy Over 24 Months. Am J Ophthalmol. 2026 May;285:288-299. doi: 10.1016/j.ajo.2026.01.038. Epub 2026 Feb 9.

  PMID: 41672367 RESULT

• Barshop BA, Ball ED, Benador N, Trauner D, Phillips S, Dohil R, Afshari NA, Roy S, Campo Fernandes B, Kohn D, Shayan K, Everett JK, Bushman FD, Midgley J, Liang H, Sawyers A, Gangoiti JA, Panchal M, Ahmed I, Cherqui S. Hematopoietic Stem-Cell Gene Therapy for Cystinosis. N Engl J Med. 2026 Feb 19;394(8):753-762. doi: 10.1056/NEJMoa2506431.

  PMID: 41707137 RESULT

MeSH Terms

Conditions

Lysosomal Storage Diseases; Cystinosis

Condition Hierarchy (Ancestors)

Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases

Limitations and Caveats

Phase 1/2 open-label single-arm study; small sample size (n=6) limits statistical inference. Results descriptive, not generalizable to pediatric patients. Most adverse events were attributable to busulfan conditioning or underlying cystinosis. Individual participant data were not uploaded due to PRS technical limitations, but are available upon request. Statistical tests were performed per protocol; results are limited by the small sample size.

Results Point of Contact

• Title: Stephanie Cherqui, Ph.D
• Organization: University of California San Diego Health

scherqui@health.ucsd.edu

8588221023

Study Officials

• Stephanie Cherqui, Ph.D.

  University of California, San Diego

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: This study will include up to 6 subjects to be dosed and follow a 3-cohort staggered treatment design with 2 subjects per cohort. The first 2 cohorts will consist of 4 adults (18 years or older), potentially followed by a cohort consisting of 2 adolescents or adults (\>14 years old).

Study Record Dates

• First Submitted: February 6, 2019
• First Posted: April 1, 2019
• Study Start: July 8, 2019
• Primary Completion: September 18, 2024
• Study Completion: September 18, 2024
• Last Updated: August 6, 2026
• Results First Posted: August 6, 2026

Record last verified: 2026-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: Beginning 3 months and ending 5 years following article publication.
• Access Criteria: Investigators whose proposed use of the data has been approved by an independent review committee identified for this purpose.

Locations

US (1)