Autologous Gene Therapy for Artemis-Deficient SCID

Phase I/II Safety and Efficacy Study of Gene Transfer for Artemis-Deficient Severe Combined Immunodeficiency (ART-SCID) in Newly Diagnosed Patients Using Self-Inactivating Lentiviral Vector (AProArt) to Transduce Autologous CD34 Hematopoietic Cells

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.

Study Overview

• Status: Recruiting
• Conditions: Severe Combined Immunodeficiency
• Intervention / Treatment: Device: CliniMACS® CD34 Reagent System cell sorter device; Drug: Busulfan; Drug: AProArt-CD34

Detailed Description

Children with SCID generally do not survive beyond the first year of life without definitive treatment. The most effective current cure is hematopoietic stem cell transplant (HCT) with a human leukocyte antigen (HLA) matched sibling. While a matched sibling HCT can successfully treat ART-SCID, fewer than 20% of affected children have such a donor, and even when a matched sibling donor is available there is often incomplete T and B cell immune reconstitution. ART-SCID is the most difficult type of SCID to cure by hematopoietic stem cell transplant using alternative donors. Engraftment typically requires intensive conditioning with high dose alkylating agents to prevent rejection and to open marrow niches. These patients also have a high risk of developing graft versus host disease (GVHD) when alternative donors are used. The great majority of patients have absent B cell reconstitution and require lifelong administration of immunoglobulin infusions. Patients with ART-SCID who do receive high doses of alkylators, especially when 2 agents are used, have poorer survival, abnormal dental development, endocrinopathies, and short stature in comparison with children exposed to no or limited alkylators or children with SCID types that are not associated with a DNA repair defect. For these reasons, a safer, more effective approach to curing ART-SCID is needed. Autologous gene-corrected hematopoeitic stem cell transplant may eliminate both the risk of GVHD and the need for alkylators to prevent rejection.

The study design is a single-cohort, longitudinal experiment using non-randomized patients treated once with a lentiviral vector for gene-correction of Artemis-deficient SCID after conditioning with low-dose busulfan. No formal control group is planned for gauging safety; rather, intensive monitoring of the initial 6 enrollees was undertaken to preclude continued accrual in the presence of safety signals. This enrollment stage was completed in 2019 with no safety signals identified, and long-term safety will be monitored for 15 years. Bone marrow stem cells will be harvested from participants, and CD34 cells will be isolated using the CliniMACS® CD34 Reagent System cell sorter device. The CD34 cells will be transduced with the AProArt lentiviral vector, and cryopreserved. Aliquots of the cells will undergo safety testing and be reserved for potency evaluation. All patients will receive busulfan conditioning targeted over 2 days to achieve a cumulative area under the curve (AUC) of 20 mg*hr/L (an ablative cumulative AUC is 60-90mg*hr/L).

Following the infusion of AProArt-transduced cells, patients will be assessed weekly through 12 weeks post-transplant and at week 16, monthly through month 6 post-transplant, every 3 months through month 24, every 6 months during years 2-5, and then annually through year 15. Assessments will include physical examination, clinical laboratory tests, collection of specimens for research studies, and completion of Quality of Life questionnaires. Neurodevelopmental testing will be performed at age-appropriate time points.

At weeks 4, 6, 8, 12, 16, and 24, research specimens will be evaluated for evidence of gene transduced peripheral blood mononuclear cells and when possible, cell lineages including T, B, NK and granulocyte/myeloid cells. If there is no evidence of gene transduced cells at 6 weeks (42 days) post infusion, planning for an alternative treatment will begin, with the final decision regarding further therapy to be based on gene-marking results at 10 weeks.

If the absolute neutrophil count is < 200/µl or platelets < 20,000/µl on 3 independent determinations after day 42 post infusion of transduced cells, the patient may receive an allogeneic hematopoeitic stem cell transplant. Patients who were neutropenic prior to conditioning (SCID-related neutropenia) but responsive to granulocyte-colony stimulating factor (GCSF) will not be considered to have failed, provided the absolute neutrophil count can be maintained above >300/µl with GCSF.

Recipients will be followed for toxicity and durable reconstitution of T and B cell immunity. Immune reconstitution of T cells will be monitored on a regular basis. Patients with evidence of clinically inadequate immune reconstitution, low vector copy number (VCN), or any other features suggesting clinically inadequate response to the initial gene therapy procedure will be offered a repeat infusion of gene-transduced cells. Conditioning regimens given prior to a repeat gene therapy procedure may include low-dose busulfan, other conditioning, or no conditioning.

Historical controls who received alternative donor allogeneic transplants as treatment for ART-SCID will serve as the comparator arm for secondary endpoints.

An independent Data Safety Monitoring Board (DSMB) has been appointed for safety monitoring of this trial. The DSMB reviews all data for safety on a regular schedule, based on numbers of enrolled subjects and conducts special urgent review of any protocol related Serious Adverse Events (SAE). In the early stage of the trial, the DSMB reviewed results of each of the first 3 cases prior to proceeding with subsequent patients.

The investigational product (IND17711) for the ART-SCID gene transfer study is not available for expanded access use. As per 21 CFR Part 312.305(3), the study management team has determined that providing the investigational product for expanded access use at this time would interfere with the conduct and completion of the clinical trial and potential development of future expanded access use. The investigational product is available to eligible patients through participation in this clinical trial.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Morton Cowan, MD; Phone Number: 415-476-2188; Email: Mort.Cowan@ucsf.edu
• Study Contact Backup: Name: Jennifer Puck, MD; Phone Number: 415 502-2090; Email: Jennifer.Puck@ucsf.edu

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94143
      • Recruiting
      • University of California, San Francisco (UCSF) Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 months and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• ≥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).

Exclusion Criteria:

• 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.

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: Gene therapy (AProArt); 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.

Device: CliniMACS® CD34 Reagent System cell sorter device; Processing of hematopoietic progenitor cells to select CD34 cells, using the CliniMACS® CD34 Reagent System, prior to infusion.; Drug: Busulfan; 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.; Other Names: Busulfex; Drug: AProArt-CD34; 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.; Other Names: lentiviral gene therapy using AProArt

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
B cell immune reconstitution by 24±2 months compared with historical control cohort of allogeneic transplant recipients	B cell immune reconstitution will be defined as cessation of immunoglobulin replacement therapy	24 months
Number of participants with T cell immune reconstitution compared with historical controls who received allogeneic transplants to treat ART-SCID.	T cell immune reconstitution will be defined as presence of both of the following: 1) a. CD3>1000/mm3; 2) CD4>500/mm3.	24 months
Event Free Survival	Events are defined as death, use of a repeat infusion of gene-corrected cells to enhance T/B cell immune reconstitution or requirement for performance of an allogeneic HCT.	24 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hematopoietic recovery in patients with ART-SCID who receive self-inactivating (SIN) lentiviral vector (AProArt)-transduced CD34 cells through a repeat infusion autologous stem cell transplant.	Patients will undergo blood tests to measure complete blood count and differential following a repeat infusion of gene corrected cells.	5 years
Adverse event (AE) profile associated with the study intervention from treatment through 15 years after the gene transfer procedure	Clinical and laboratory AEs as measured by CTCAE V4	15 years
Number of participants with B cell reconstitution beyond 24 months, including B cell numbers and function	B cell reconstitution will be defined as presence of at least two of the following: 1) B cell number >40/mm3; 2) Cessation of immunoglobulin replacement therapy; 3) Protective specific antibody responses. The number of participants who meet the definition for B cell reconstitution will be tabulated.	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.	Achievement of final target cumulative AUC of 20±2 mg*hr/L in approximately 90% of subjects	42 days
Repertoire diversity of T and B cells, as assessed by analyzing T cell receptor gene variable beta sequence (TCR-Vb) and immunoglobulin heavy chain (IGH) rearranged receptors and calculating diversity Shannon Index.	Measured by deep sequencing of the T cell receptor (TCR) gene variable beta sequence (TCR-Vb) and immunoglobulin heavy chain (IGH) rearranged receptors. The diversity Shannon Index is expected to be above 7.5 by 24±2 months post treatment in 90% of patients.	24 months
Determine if B cell receptor diversity at 6 months is predictive of B cell reconstitution over 15 years by analyzing B cell receptor gene variable beta sequence and immunoglobulin heavy chain rearranged receptors and calculating diversity Shannon Index.	A Shannon Index >5 is expected to be a biomarker for B cell reconstitution. B cell receptor diversity will be measured throughout study participation.	15 years
Determine if at 6 months T cell receptor (TCR) diversity and/or absolute CD3, CD4, naïve CD4 counts predict T cell reconstitution at 24 months or need for 2nd treatment throughout the 15 year follow-up period.	TCR-Vb diversity and absolute CD3, CD4 and naïve CD4 counts will be measured at 6 months. T cell reconstitution will be measured throughout study participation.	15 years
Stability of mean vector copy number (VCN) and the location of vector integration sites in sorted T, B, and natural killer (NK) cells, granulocytes and monocytes in peripheral blood over time after infusion of transduced HSC.	Mean vector copy number (VCN) and the location of vector integration sites will be measured at 6±1, 12±1 and 24±2 months and then annually through 15 years after infusion of AProArt-CD34. The mean VCN should be >0.5 copies/cell in T and B cells and >0.01 in NK, myeloid and granulocytes by 24±2 months post treatment.	24 months
Characterization of insertion sites in multiple cell lineages as an indicator of diversity, multilineage engraftment, and tabulation of any clonal expansion that might indicate development of a malignancy.	Insertion sites will be measured at 6±1, 12±1, 24±2 months, and annually through 15 years after infusion of AProArt-CD34. Cell insertion sites are expected to be diverse with no clone representing >20% of a lineage at 24 months.	24 months
Potential benefit of prophylactic sirolimus in reducing the incidence of transient autoimmune hemolytic anemia (AIHA) post infusion of AProArt-CD34, as assessed by number of participants with clinical diagnosis of AIHA.	Incidence of autoimmune hemolytic anemia by 24±2 months post infusion following administration of prophylactic sirolimus, as assessed by monitoring of hemoglobin, direct and indirect Coombs, reticulocyte, and lactate dehydrogenase results. Incidence of AIHA requiring treatment is expected to be <40% of patients on prophylactic sirolimus.	24 months
Measurement of radiation sensitivity in peripheral blood NK cells for development and validation of a rapid functional assay for radiation-sensitive SCID.	Development and validation of an assay for radiation sensitive SCID in peripheral blood NK cells	24 months
Potency of AProArt-CD34 as indicated by capacity for in vitro differentiation of participant specimens into T cells and assessment of average VCN as a surrogate marker for potency.	Demonstration that post-transduction patient CD34+ cells have the capacity for in vitro differentiation into T cells and that average VCN is a surrogate marker for potency. One or more potency assays will be developed and validated for AProArt-transduced CD34+ HSC that give results within 52 days of transduction, and correlation of these with VCN obtained at 6 and 14 days post transduction with AProArt.	5 years
Effects of targeted low exposure busulfan conditioning on patient growth/stature	Patient height (cm) and weight (kg) will be measured and compared with norms for age	5 years
Effects of busulfan on patient dental development	Dental histories and clinical notes will be reviewed to compare permanent tooth development will be compared with development norms for age from age 5 through age 15 years	5 years
Patient reported outcome of undergoing treatment with gene-corrected cells as assessed by the PedsQL questionnaires.	Age-appropriate Pediatric Quality of Life Inventory (PedsQL) questionnaires will be administered at baseline and years 1, 2, 4, 8, 10, 12, and 15. Four domains (Physical Functioning, Emotional Functioning, Social Functioning, and School Functioning) are reverse-scored on a 5-point Likert scale and transformed to a 0-100 scale, with higher scores indicating better outcomes.	5 years
Family impact of undergoing treatment with gene-corrected cells.	The Pediatric Quality of Life Inventory (PedsQL) Family Impact module will be administered at baseline and years 1, 2, 4, 8, 10, 12, and 15. Responses are indicated on a 5-point Likert scale and transformed to a 0-100 scale, with higher scores indicating better outcomes.	15 years
Effects of the study intervention on neurodevelopment over time	Neurodevelopment will be assessed at ages 3, 5, 8, 11, 14 and 17 years using applicable age-appropriate instruments (Vineland Adaptive Behavior Scales, Behavior Rating Inventory of Executive Functioning, Behavioral Assessment for Children, Bayley Scales of Infant Development, Wechsler Intelligence Scales, California Verbal Learning Test, Conners Continuous Performance Test, Delis-Kaplan Executive Function System, and Wide Range Achievement Test). Results will be compared with norms for ages 18 months and ages 3, 5, 8, 11, 14 and 17 years.	5 years

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Investigators: Principal Investigator: Morton Cowan, MD, University of California, San Francisco

Publications and helpful links

General Publications

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Study record dates

Study Major Dates

• Study Start (Actual): May 31, 2018
• Primary Completion (Estimated): June 1, 2038
• Study Completion (Estimated): June 1, 2038

Study Registration Dates

• First Submitted: May 3, 2018
• First Submitted That Met QC Criteria: May 15, 2018
• First Posted (Actual): May 29, 2018

Study Record Updates

• Last Update Posted (Actual): February 13, 2026
• Last Update Submitted That Met QC Criteria: February 11, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: gene therapy; autologous stem cell transplant; Artemis-deficient Severe Combined Immunodeficiency
• Additional Relevant MeSH Terms: Primary Immunodeficiency Diseases; Genetic Diseases, Inborn; Metabolic Diseases; Immune System Diseases; Infant, Newborn, Diseases; Immunologic Deficiency Syndromes; DNA Repair-Deficiency Disorders; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Severe Combined Immunodeficiency; Sulfur Compounds; Organic Chemicals; Hydrocarbons, Acyclic; Hydrocarbons; Alkanes; Alcohols; Butylene Glycols; Glycols; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Sulfonic Acids; Sulfur Acids; Busulfan
• Other Study ID Numbers: 17-22799; CLIN2-10830 (Other Grant/Funding Number: California Institute of Regenerative Medicine); CLIN2-17127 (Other Grant/Funding Number: California Institute of Regenerative Medicine)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie the results reported in scientific journals (text, tables, figures, and appendices) after de-identification.
• IPD Sharing Time Frame: Beginning 3 months and ending 5 years following article publication
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes