Glutamine Supplementation in People With Immune Dysregulation

Atopic dermatitis (AD) is a chronic, relapsing, inflammatory skin condition that typically begins in infancy or early childhood and can be highly debilitating with a marked reduction in quality of life. Current treatment modalities for AD include frequent use of skin moisturizers such as creams or emollients, topical corticosteroids and topical calcineurin inhibitors, systemic immunosuppressive drugs, and, in select cases of refractory disease, wet wrap therapy. The available systemic treatments for AD when topical treatment fails can have substantial adverse effects and are not always effective. The search for targeted therapies based on pathway disruptions in patients could present opportunities to provide therapies on a more personalized basis, tailored to the pathogenic pathways. Based on prior studies, we have demonstrated that supplemental glutamine has potential as an effective AD treatment in patients with caspase activation and recruitment domain (CARD) gene mutations. Prior studies have demonstrated that loss of CARD signaling leads to a decrease in the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway. Glutamine supplementation can normalize this defect in mTORC1. The CARD11 BCL10 MALT1 (CBM) signalosome complex is a critical component of mTORC1 activation. Some patients with gene mutations affecting the CBM complex do not develop AD but do develop other symptoms of immunoregulation and may also benefit from glutamine supplementation. We will conduct a phase 1, open-label study to investigate the use of supplemental glutamine in patients with immune dysregulation. Subjects 5 to 65 years of age will take oral glutamine daily for 3 months. To assess the role of the mTORC1 pathway in response to glutamine supplementation, we will enroll 3 groups of patients: 1) those with AD and a defect in mTORC1 signaling or a mutation in the CBM complex; 2) those with AD who do not have a defect in mTORC1 signaling or a mutation in the CBM complex; and 3) those who have a defect in mTORC1 signaling or a mutation in the CBM complex and do not have AD. Subjects will complete a daily symptom diary for 1 month before starting glutamine to document baseline disease status. Disease severity will be assessed at baseline, at the end of glutamine supplementation, and 1 and 3 months after completing the glutamine regimen. Blood will be collected periodically for safety, tolerability, and research assessments.