Autologous Gene Therapy for Artemis-Deficient SCID

NCT03538899 | Recruiting Phase 1 DMC FDA Drug FDA Device

• 3 other identifiers: 17-22799CLIN2-10830CLIN2-17127
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

This study aims to determine if a new method can be used to treat Artemis-deficient Severe Combined Immunodeficiency (ART-SCID), a severe form of primary immunodeficiency caused by mutations in the DCLRE1C gene. This method involves transferring a normal copy of the DCLRE1C gene into stem cells of an affected patient. Participants will receive an infusion of stem cells transduced with a self-inactivating lentiviral vector that contains a normal copy of the DCLRE1C gene. Prior to the infusion they will receive sub-ablative, dose-targeted busulfan conditioning. The study will investigate if the procedure is safe, whether it can be done according to the methods described in the protocol, and whether the procedure will provide a normal immune system for the patient. A total of 24 newly diagnosed patients will be enrolled at the University of California San Francisco in this single-site trial and will be followed for 15 years post-infusion. It is hoped that this type of gene transfer may offer improved outcomes for ART-SCID patients who lack a brother or sister who can be used as a donor for stem cell transplantation or who have failed to develop a functioning immune system after a previous stem cell transplant.

Conditions

Severe Combined Immunodeficiency

Keywords

Artemis-deficient Severe Combined Immunodeficiency; gene therapy; autologous stem cell transplant

Outcome Measures

Primary Outcomes (1)

• To demonstrate that ART-SCID patients receiving AProArt-CD34 infusion have superior overall survival (OS) at 24 months post treatment with AProArt-CD34 versus the established outcome of 0% OS for patients who receive no treatment for ART-SCID

  Patient survival status and (if applicable) cause of death will be recorded to assess overall survival.

  24 months

Secondary Outcomes (3)

• B cell immune reconstitution by 24±2 months compared with historical control cohort of allogeneic transplant recipients

  24 months

• Number of participants with T cell immune reconstitution compared with historical controls who received allogeneic transplants to treat ART-SCID.

  24 months

• Event Free Survival

  24 months

Other Outcomes (17)

• Adverse event (AE) profile associated with the study intervention from treatment through 15 years after the gene transfer procedure

  15 years

• Number of participants with B cell reconstitution beyond 24 months, including B cell numbers and function

  15 years

• Efficacy of targeting low exposure busulfan in infants and children, calculated by percentage of participants whose treatment meets study parameters using a validated population pharmacokinetic model to calculate individualized busulfan clearance.

  42 days

Study Arms (1)

Gene therapy (AProArt)

EXPERIMENTAL

Gene Transfer for Artemis-Deficient Severe Combined Immunodeficiency (ART-SCID) Using a Self-Inactivating Lentiviral Vector (AProArt) to Transduce Autologous CD34 Hematopoietic Cells. The CliniMACS® CD34 Reagent System sorter device will be used to select CD34 cells. Patients will be conditioned with low dose busulfan prior to transplant.

Drug: AProArt-CD34; Device: CliniMACS® CD34 Reagent System cell sorter device; Drug: Busulfan

Interventions

AProArt-CD34 DRUG

Participants will undergo infusion with autologous hematopoietic cells transduced with a lentiviral vector, AProArt, which contains the correct form of DCLRE1C complementary deoxyribonucleic acid DNA, after receiving sub-ablative, exposure-targeted busulfan conditioning.

Also known as: lentiviral gene therapy using AProArt

Gene therapy (AProArt)

CliniMACS® CD34 Reagent System cell sorter device DEVICE

Processing of hematopoietic progenitor cells to select CD34 cells, using the CliniMACS® CD34 Reagent System, prior to infusion.

Gene therapy (AProArt)

Busulfan DRUG

Busulfan is a cell cycle non-specific alkylating antineoplastic agent, in the class of alkyl sulfonates. Patients will receive low-dose busulfan conditioning targeted over 2 days to achieve a cumulative area under the curve (AUC) of 20 mg\*hr/L.

Also known as: Busulfex

Gene therapy (AProArt)

Eligibility Criteria

• Age: 2 Months+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• ≥2.0 months of age at initiation of busulfan conditioning
• New diagnosis of typical or minimally leaky ART-SCID, as defined by the criteria below:
• Artemis deficiency with bi-allelic pathogenic or likely pathogenic mutations in DCLRE1C; AND
• CD3 count \< 50 autologous cells/µL (typical ART-SCID) OR spontaneous maternal chimerism, OR CD3 count \>50/µL and \<300/uL and with restricted T cell receptor Vb diversity; AND
• CD45 cell response to mitogens (PHA) \< 50% of the lower limit of normal range for the lab (leaky ART-SCID).
• No medically eligible HLA-identical sibling with a normal immune system who could serve as an allogeneic bone marrow donor (applies to newly diagnosed patients only).

You may not qualify if:

• Presence of a medically eligible HLA-matched sibling
• Evidence of HIV infection by polymerase chain reaction or p24 antigen testing.
• Unable to tolerate general anesthesia and/or marrow harvest or insertion of central venous catheter.
• Any one of liver function tests AST, ALT, gamma-glutamyl transpeptidase (GGT) \>5X the upper limit of normal for lab and/or total bilirubin \>2.0 mg/dl (not due to Gilbert's) at the time of planned initiation of busulfan conditioning unless the elevated LFTs are considered to be due to medication, a viral infection for which there is no treatment other than reconstituting T cell immunity, or maternal GVHD.
• Presence of any severe medical conditions making a patient unsuitable for busulfan administration
• Presence of a recognized second gene mutation that results in an autosomal dominant or recessive disorder intrinsic to hematopoietic cells and that could be treated by an allogeneic HCT.
• Presence of a medical condition indicating that survival is predicted to be less than 4 months, such as the requirement for mechanical ventilation, severe failure of a major organ system, or evidence of a serious, progressive infection that is refractory to medical therapy.
• A social situation indicating that the family may not be able to comply with protocol procedures and recommended medical care and follow-up.
• Other conditions which in the opinion of the Principal Investigator and/or co-investigators, contra-indicate the infusion of transduced cells or study participation.

Sponsors & Collaborators

• University of California, San Francisco: lead

Study Sites (1)

University of California, San Francisco (UCSF) Children's Hospital

San Francisco, California, 94143, United States

RECRUITING

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  BACKGROUND

• Mamcarz E, Zhou S, Lockey T, Abdelsamed H, Cross SJ, Kang G, Ma Z, Condori J, Dowdy J, Triplett B, Li C, Maron G, Aldave Becerra JC, Church JA, Dokmeci E, Love JT, da Matta Ain AC, van der Watt H, Tang X, Janssen W, Ryu BY, De Ravin SS, Weiss MJ, Youngblood B, Long-Boyle JR, Gottschalk S, Meagher MM, Malech HL, Puck JM, Cowan MJ, Sorrentino BP. Lentiviral Gene Therapy Combined with Low-Dose Busulfan in Infants with SCID-X1. N Engl J Med. 2019 Apr 18;380(16):1525-1534. doi: 10.1056/NEJMoa1815408.

  PMID: 30995372 BACKGROUND

• Cowan MJ, Yu J, Facchino J, Fraser-Browne C, Sanford U, Kawahara M, Dara J, Long-Boyle J, Oh J, Chan W, Chag S, Broderick L, Chellapandian D, Decaluwe H, Golski C, Hu D, Kuo CY, Miller HK, Petrovic A, Currier R, Hilton JF, Punwani D, Dvorak CC, Malech HL, McIvor RS, Puck JM. Lentiviral Gene Therapy for Artemis-Deficient SCID. N Engl J Med. 2022 Dec 22;387(25):2344-2355. doi: 10.1056/NEJMoa2206575.

  PMID: 36546626 BACKGROUND

MeSH Terms

Conditions

Severe Combined Immunodeficiency

Interventions

Busulfan

Condition Hierarchy (Ancestors)

Primary Immunodeficiency Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Infant, Newborn, Diseases; DNA Repair-Deficiency Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Butylene Glycols; Glycols; Alcohols; Organic Chemicals; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Sulfonic Acids; Sulfur Acids; Sulfur Compounds

Study Officials

• Morton Cowan, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Morton Cowan, MD

CONTACT

415-476-2188; Mort.Cowan@ucsf.edu

Jennifer Puck, MD

CONTACT

415 502-2090; Jennifer.Puck@ucsf.edu

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 Emeritus

Model Details: Longitudinal study of autologous stem cell transplant of cells transduced with corrected DCLRE1C gene using a self-inactivating lentiviral vector (AProArt). The CliniMACS® CD34 Reagent System cell sorter device will be used to select CD 34 cells. Sub-ablative busulfan will be used for pre-transplant conditioning.

Study Record Dates

• First Submitted: May 3, 2018
• First Posted: May 29, 2018
• Study Start: May 31, 2018
• Primary Completion (Estimated): June 1, 2038
• Study Completion (Estimated): June 1, 2038
• Last Updated: February 13, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Beginning 3 months and ending 5 years following article publication
• Access Criteria: Researchers can submit a request for access to the study Steering Committee. If the proposal is determined to be methodologically sound, data requestors will need to sign a data access agreement prior to gaining access.

Locations

US (1)