Autologous Gene Therapy for Artemis-Deficient SCID

• Status: Recruiting
• Trial end date: 2038-06-01
• Target enrollment: 0
• Participant gender: All

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 25 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.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University of California, San Francisco
• Treatments: Busulfan

Criteria

Inclusion Criteria:

• ≥2.0 months of age at initiation of busulfan conditioning

• Diagnosis of typical or leaky ART-SCID:

Newly diagnosed ART-SCID patients must have:

• Artemis deficiency; AND

• CD3 count < 300 autologous cells/µL (typical ART-SCID) OR spontaneous maternal chimerism, OR CD3 count >300/µL but with restricted T cell receptor Vb diversity, defined as 18/24 or fewer polyclonal families.

AND - CD45 cell response to mitogens (PHA) < 50% of the lower limit of normal range for the lab (leaky ART-SCID).

Patients diagnosed with ART-SCID per the criteria above who have failed an allogeneic transplant (including an HLA matched sibling transplant) may participate if they meet the criteria below:

• Are at least 3 months post allogeneic hematopoeitic stem cell transplant without evidence of engraftment of allogeneic donor cells (excluding maternal cells)

OR are engrafted but have at least 2 of the following 4 conditions:

• Declining CD3 donor chimerism with at least 3 evaluations separated by at least 1 month prior to time of enrollment OR < 5% overall donor chimerism in blood and marrow at ≥3 months post transplant.

• Incompletely reconstituted T cell immunity at ≥6 months (1 of the following 2):

• CD4 < 200/μL AND CD45 cell PHA < 50% of the lower limit of normal for lab;

• CD4 CD45RA < 20% of total CD4 cells OR T cell receptor Vb diversity is restricted, defined as 18/24 or fewer polyclonal families.

• No donor B cells OR lack of B cell function (immunoglobulin M isohemagglutinins < 1:8 (not blood type AB) AND immunoglobulin A (IgA) or IgM values below reference range for age AND if not receiving intravenous immunoglobulin (IVIG), no protective level of antibody to tetanus immunization x2).

• Clinical manifestations consistent with persistent T and B cell immunodeficiency e.g., chronic infection including norovirus, cytomegalovirus, human herpes virus 6; OR acute or recurrent infection (e.g., PJP), bronchiectasis, chronic sinusitis.

AND

• Have no prior exposure to high dose busulfan (≥10 mg/kg total dose or average cumulative exposure of ≥40 mg*hr/L). If the total cumulative AUC including previous busulfan exposure plus the dose to be administered in this protocol is predicted to be ≤60 mg*hr/L, then patient would be eligible providing other criteria are satisfied.

• 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).

Written informed consent according to guidelines of the Institutional Review Board (IRB).

Exclusion Criteria:

• Liver function tests (aspartate aminotransferase, alanine transaminase, gamma-glutamyl transferase) > three times the upper limit of normal for lab and/or total bilirubin >1.50 mg/dl at the time of planned initiation of busulfan conditioning.

• Prior history of veno-occlusive disease (Sinusoidal obstruction syndrome) of the liver.

• Medically eligible HLA-matched sibling (applies to newly diagnosed patients only).

• Evidence of HIV infection by polymerase chain reaction or p24 antigen testing.

• Unable to tolerate general anesthesia and/or marrow harvest or peripheral blood stem cell collection (apheresis) or insertion of central venous catheter.

• 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.

• Pregnancy

• 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.