Thymus Transplantation in DiGeorge Syndrome #668
Condition: DiGeorge Syndrome; Complete Typical DiGeorge Anomaly
MeSH terms: DiGeorge Syndrome; Syndrome
Intervention: Cultured Thymus Tissue for Implantation (CTTI)
Intervention description: Cultured thymus tissue for implantation (CTTI) (previously described as transplantation) is done using allogeneic cultured postnatal tissue from unrelated thymus donors. Thymus tissue, the thymus donor, & thymus donor's birth mother were screened for safety. Approximately 2-3 weeks post-harvest thymus slices were implanted into the recipient's quadriceps. Dose was number of grams of cultured thymus tissue divided by the recipient's weight in kilograms. Minimum dose was 4 g/m2. Maximum dose 18g/m2. At time of CTTI, a skin biopsy was obtained to look for preexisting T cells. 2-3 months post-CTTI allograft biopsy to evaluate for thymopoiesis & graft rejection. At time of biopsy, skin biopsy done to look for T cell clonal populations. Post-CTTI, subjects followed by routine research immune evaluations, using blood samples for approximately 2 years.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 26.0
Sex: All
Healthy volunteers: No
Keywords: Thymus Transplantation; DiGeorge Syndrome; Athymia; Low T cell numbers; Immunoreconstitution; Primary immunodeficiency; DiGeorge Anomaly; Complete DiGeorge; Typical DiGeorge; Cultured Thymus Tissue Implantation (CTTI)

Summary:

      The study purpose is to determine whether cultured thymus tissue implantation (CTTI) is
      effective in treating typical complete DiGeorge syndrome.
    

Eligibility criteria:

        Inclusion Criteria:

          -  The subject's parent(s) signed the ICF.

          -  For a diagnosis of DiGeorge Syndrome (DGS), the subject had one of the following:

               -  Heart defect

               -  Hypoparathyroidism

               -  22q11 hemizygosity

               -  10p13 hemizygosity

               -  Coloboma, heart defect, choanal atresia, growth and development retardation,
                  genital hypoplasia, ear anomalies/ deafness CHARGE association mutation (CHD7
                  deletion);

               -  PHA proliferative responses less than 20-fold above background.

          -  Subjects with typical Complete DiGeorge Anomaly (cDGA) had to have one of the
             following on 2 separate occasions:

          -  Circulating CD3+ T cells by flow cytometry < 50/mm3 or PHA < 20-fold over background

               -  If CD3+ were > 50/mm3, then CD45RA+ (cluster of differentiation 45RA) CD62L+ had
                  to be < 50/mm3

               -  Or T cell receptor rearrangement excision circles (TRECs) by PCR had to be < 100
                  per 100,000 CD3+ cells.

          -  Subjects with atypical cDGA had to have both of the following with 2 studies each:

               -  Circulating CD3+ T cells by flow cytometry > 500/mm3 and CD45RA+ CD62L+ CD3+ T
                  cells < 50/mm3 and TRECs less than 100 per 100,000 CD3+ cells.

               -  T cell proliferative response to PHA more than 20-fold over background.
                  Circulating CD3+ T cells by flow cytometry > 500/mm3 and CD45RA+ CD62L+ CD3+ T
                  cells < 50/mm3 and TRECs less than 100 per 100,000 CD3+ cells.

               -  T cell proliferative response to PHA more than 20-fold over background. While T
                  cell response to PHA might have been seen, eligible subjects were to have no T
                  cell proliferative response to antigens (less than 20-fold response) and were to
                  have serious clinical problems related to immunodeficiency, such as opportunistic
                  infection or failure to thrive.

        Exclusion Criteria:

          -  Subjects on ventilators, with tracheostomies, with cytomegalovirus (CMV) infections,
             or requiring ongoing steroids could still be enrolled, but their data were to be
             analyzed separately

          -  Subjects who had heart surgery < 4 weeks prior to transplant

          -  Heart surgery anticipated within 3 months of the proposed time of transplantation

          -  Ongoing parenteral steroid therapy between enrollment and transplantation

          -  Present or past lymphadenopathy

          -  Rash associated with T cell infiltration of the dermis and epidermis

          -  Rejection by the surgeon or anesthesiologist as surgical candidates

          -  Lack of sufficient muscle tissue to accept a transplant of 4 g/m2 body surface area
             (BSA) of the recipient

          -  Prior attempts at immune reconstitution, such as bone marrow transplantation or
             previous thymus transplantation

          -  Human immunodeficiency virus (HIV) infection