Serum-Free Thymus Transplantation in DiGeorge Anomaly

Study Overview
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Brief Summary
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The study purpose is to determine if thymus tissue cultured in a serum-free (SF) solution is a safe and effective treatment for atypical and typical complete DiGeorge anomaly. [Funding Source - FDA OOPD]

Detailed Description
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Complete DiGeorge anomaly is a congenital disorder characterized by athymia. Without successful treatment, patients remain immunodeficient and usually die by age 2 years. In typical complete DiGeorge subjects who have no T cells, thymus transplantation without immunosuppression has resulted in diverse T cell development and good T cell function. In atypical complete DiGeorge subjects who have no thymus, a rash, and some T cells that presumably developed extrathymically, thymus transplantation with immunosuppression has resulted in diverse T cell development and good T cell function. Thus far, thymus transplantation studies have used thymus cultured in fetal bovine serum (FBS medium). This protocol's purpose is to determine whether transplanted thymus cultured in serum free medium can safely support thymopoiesis and T cell reconstitution as does FBS medium cultured thymus tissue in DiGeorge anomaly subjects. This protocol includes 2 arms: atypical DiGeorge subjects who will receive immunosuppression and thymus transplantation; and, typical complete DiGeorge subjects who will receive thymus transplantation without immunosuppression. Serum free medium use would reduce concerns of animal product exposure including potential exposure to bovine spongiform encephalopathy(BSE).

Official Title
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Phase I Serum-Free Cultured Thymus Transplantation in DiGeorge Anomaly, IND9836

Conditions
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DiGeorge Anomaly

Intervention / Treatment
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* Biological: Serum Free Thymus Transplantation with Immunosuppression
* Other: Serum Free Thymus Transplantation without immunosuppression


Participation Criteria
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Eligibility Criteria
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Thymus Recipients Inclusion: Complete DiGeorge anomaly diagnosis Must have one of following: congenital heart disease hypocalcemia requiring replacement 22q11 or 10p13 hemizygous CHARGE Atypical Arm: Must have, or have had, rash. If rash present, skin biopsy must show T cells. If rash resolved, must have >50/cumm T cells; & <50/cumm naive T cells or <5% total PHA response must be <40000 counts per minute(cpm) on immunosuppression; or, <75000cpm off immunosuppression. PHA test must be done 2x CD45RA+CD62L+ CD3+ T cells must be <50/mm3; or, <5% of total CD3. Test must be done 2x Typical Arm: PHA response <20 fold or <5,000cpm Circulating CD3+CD45RA+CD62L+T cells <50/mm3 or <5% total T cells 2 tests of T cells & PHA response must show similar results Biological Mother Inclusion: -Must be recipient's biological mother Thymus Recipient Exclusion: Heart surgery <4 weeks pre-transplant or within 3 months post-transplant Rejection by surgeon or anesthesiologist as surgical candidates Lack of sufficient muscle tissue to accept transplant Medical condition does not allow to undergo a biopsy HIV CMV(>500 copies/ml blood by PCR on 2 tests) Ventilator dependence GVHD Maternal T cells >20% of total T cells Prior immune reconstitution attempts (e.g., BMT, prior thymus transplant) Hypoparathyroidism meeting criteria for combined thymus/parathyroid transplant & parents desiring it RSV or parainfluenza virus Enterovirus or Adenovirus in stool Biological Mother Exclusion: -Unwillingness to sign consent or provide blood/buccal samples

Ages Eligible for Study
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Maximum Age: 2 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Atypical Complete DiGeorge<br>Thymus Transplantation with Immunosuppression | Biological: Serum Free Thymus Transplantation with Immunosuppression<br>* Cyclosporine pre-transplant (trough 180-220ng/ml) until naive T cells develop. Subjects >4,000/cumm T cells, pre-transplant methylprednisolone or prednisolone 1-2mg/kg/day. All subjects pre-transplant days -5,-4,-3: 3 doses 2mg/kg rabbit anti-thymocyte globulin. Thymus tissue (unrelated donor), donor, & donor's mother screened for safety. Transplant under general anesthesia into quadriceps. First 2 subjects, FBS cultured thymus is transplanted in 1 leg & serum free (SF) in other. After first 2 subjects >10% naïve T cells, 3rd receives only SF thymus. After 3rd subject >10%naive T cells, 4th subject transplanted. Thymus dose 4-18 grams/m2 body surface area. Thymus biopsy 8-12 weeks post-transplant. Skin biopsy at time of transplant & thymus biopsy. Followed by immune evaluations.<br>* Other names: Thymus Tissue Transplant;|
| Experimental: Typical Complete DiGeorge<br>Thymus Transplantation without Immunosuppression | Other: Serum Free Thymus Transplantation without immunosuppression<br>* Thymus tissue (unrelated donor), donor, & donor's mother screened for safety. Transplant under general anesthesia into quadriceps. First 2 subjects: FBS cultured thymus transplanted in 1 leg & serum free cultured thymus in other leg. After first 2 subjects have thymopoiesis in serum-free biopsy, >10% naïve T cells, 3rd subject receives only serum free cultured thymus. After 3rd subject >10% naive T cells, 4th subject receives transplant of only serum free cultured thymus. Dose 4-18grams/m2 body surface area. At time of transplant, skin biopsy. Allograft biopsy & skin biopsy done 8 to 12 weeks post-transplant. (Graft biopsy not done if subject medically unstable.) Post-transplant, subjects followed by immune evaluations, using blood samples, for two years.<br>* Other names: Thymus Tissue Transplant;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival | Survival at one year post thymus transplantation. | One year post-thymus transplantation. | 
| Incidence of graft-versus-host-disease (GVHD). | Development of graft versus host disease in first year after transplantation associated with T cells from the thymus donor. | One year post-thymus-transplantation. | 
| Thymopoiesis or graft rejection on biopsy. | Graft rejection analysis by biopsy at 2 months post-thymus transplantation. | Two months post-thymus transplantation. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of autoimmune disease. | Incidence of autoimmune disease by year 2 after transplantation Cytopenias as assessed by complete blood counts and differential. Thyroid disease as assessed by thyroid function tests | By two years post-thymus transplantation. | 
| Immune outcomes: T cell development; evaluate T cell numbers, diversity, and function. | Number of naïve CD4 T cells at one year after transplantation Number of total CD4 T cells at one year after transplantation Proliferative response to PHA at one year after transplantation TCRBV diversity by spectratyping measured by DKL score at one year after transplantation | One year post-thymus transplantation. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Thymus Transplantation, DiGeorge Anomaly, Athymia, Low T cell numbers, Immunoreconstitution, Immunodeficiency