Rapamycin Treatment for Activated Phosphoinositide 3-Kinase δ Syndrome

Study Overview
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Brief Summary
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The purpose of this proposed research is to evaluate the efficacy and safety of the rapamycin therapy in patients with activated phosphoinositide 3-kinase δ syndrome (APDS).

Detailed Description
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Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described autosomal dominant primary immunodeficiency (PID), caused by the mutations in PIK3CD gene. The manifestations of APDS mainly include recurrent respiratory tract infections, persistent Epstein-Barr virus (EBV)/ cytomegalovirus (CMV)infections, lymphadenopathy, splenomegaly, CD4+T cells lymphopenia, and hyper-IgM syndrome. PIK3CD encodes p110δ, the catalytic subunit of phosphatidylinositol 3-kinase (PI3K) which mainly expresses in leukocytes, being critical for their proliferation, activation and survival. Gain-of-function (GOF) PIK3CD mutations lead to PI3Kδ hyperactivity, with the downstream mediators Akt and mammilian target of rapamycin (mTOR) hyperphosphorylated. Patient-derived lymphocytes had increased levels of phosphatidylinositol 3,4,5-trisphosphate and phosphorylated AKT protein. Hyperactivation of mTOR increases phosphorylation of kinases and increased glycolysis that results in enhanced proliferation and senescence of terminally differentiated CD8+ Tcell populations. The optimal treatment for these APDS patients is not yet determined; however, there are many kinds of therapeutic approaches (anti-infection prophylaxis, immunoglobulin replacement, conventional immunosuppressants, PI3K/mTOR inhibitors and hematopoietic stem cell transplantation). The APDS patients frequently receive treatment with immunoglobulin replacement and antibiotics. Hematopoietic stem cell transplantation (HSCT) has been currently curative in APDS patients; however, longer-term follow-up to determine the degree of donor chimerism and efficacy is required. There are several subjects without a prompt suitable matched donor or for whom the critical disease conditions force to postpone HSCT.The mammalian/mechanistic target of inhibitor rapamycin was reported to improve circulating T-cell profiles. Individual patients in previous studies experienced a decrease in nonneoplastic lymphoproliferation while taking rapamycin. The investigators in this study hope to evaluate the efficacy and safety of rapamycin in the treatment for carefully selected patients with APDS.

Official Title
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Efficacy and Safety of Rapamycin Therapy for Patients With Activated Phosphoinositide 3-Kinase δ Syndrome

Conditions
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Activated PI3K-delta Syndrome, Immunodeficiency Primary

Intervention / Treatment
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* Drug: Rapamycin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with activated phosphoinositide 3-kinase δ syndrome No more than 18 years old Exclusion Criteria: Patients with serious fungous infection Patients with serious complications Lack of parental consent

Ages Eligible for Study
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Maximum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rapamycin<br>Treatment for patients with activated phosphoinositide 3-kinase δ syndrome | Drug: Rapamycin<br>* Gain-of-function (GOF) PIK3CD mutations lead to PI3Kδ hyperactivity, with the downstream mediators Akt and mTOR hyperphosphorylated. The mammalian/mechanistic target of rapamycin inhibitor rapamycin may be effective to control the progress of this disease.<br>* Other names: Sirolimus;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of Recurrent Infections | Frequency of recurrent infections of the patients as indicators of rapamycin efficacy. | 5 years | 
| Hepatosplenomegaly | Changes in hepatosplenomegaly with rapamycin treatment. | 5 years | 
| Lymphocyte subset | The changes of lymphocytes subset were evaluated by flow cytometry. | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events | Unexpected toxic adverse events during and after using rapamycin | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Activated PI3K-delta Syndrome, Immunodeficiency Primary, Akt/mTOR pathway, Rapamycin Therapy, Hyperphosphorylation