Gene therapy for treating Artemis-deficient Severe Combined Immunodeficiency

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 is testing a new gene therapy to see if it can help children with Artemis-deficient Severe Combined Immunodeficiency build a normal immune system using their own corrected stem cells.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 24 (estimated)
• Ages: 2 Months and up
• Sex: All
• Sponsor: University of California, San Francisco (Academic / other)
• Locations: 1 site (San Francisco, California)
• Trial ID: NCT03538899 on ClinicalTrials.gov

What this trial studies

This study aims to treat Artemis-deficient Severe Combined Immunodeficiency (ART-SCID) by transferring a normal copy of the DCLRE1C gene into the patient's own stem cells. Participants will undergo a conditioning regimen with sub-ablative busulfan before receiving an infusion of gene-corrected stem cells. The trial will assess the safety and efficacy of this approach in providing a normal immune system. A total of 24 newly diagnosed patients will be enrolled at the University of California San Francisco and followed for 15 years post-infusion.

Who should consider this trial

Good fit: Ideal candidates are children diagnosed with typical or leaky ART-SCID who are at least 2 months old and meet specific immunological criteria.

Not a fit: Patients who have already undergone an allogeneic transplant with evidence of donor cell engraftment may not benefit from this study.

Why it matters

Potential benefit: If successful, this therapy could provide a functional immune system for patients with ART-SCID, potentially eliminating the need for lifelong immunoglobulin therapy.

How similar studies have performed: Other studies using gene therapy for different types of SCID have shown promising results, indicating potential success for this novel approach.

Eligibility criteria

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.

Where this trial is running

San Francisco, California

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

Study contacts

• Principal investigator: Morton Cowan, MD — University of California, San Francisco
• Study coordinator: Morton Cowan, MD

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