Ustekinumab (Anti-IL-12/23p40 Monoclonal Antibody) in Patients With Leukocyte Adhesion Deficiency Type 1 (LAD1) Who Have Inflammatory Pathology

Overview

Background: The disease leukocyte adhesion deficiency type 1 (LAD1) affects white blood cells. Those are immune system cells. In people with LAD1, white blood cells do not properly communicate with the rest of the body. This causes uncontrolled inflammation, particularly in the gums. People with LAD1 can get frequent infections and tend to lose their teeth before adulthood. Researchers want to see if a drug called ustekinumab helps people with LAD1. Objective: To study the safety and tolerability of ustekinumab in treating gum inflammation in people with LAD1. Eligibility: People ages 12 65 with LAD1 Design: Participants will be screened with: * Medical history * Physical exam * Oral exam * A scan of the chest, abdomen, and pelvis for possible infection * Blood and urine tests The baseline visit will take 2 days. Participants will: * Repeat most screening tests * Have a skin exam * Have small pieces of their gums removed (biopsy) * Have mouth fluids collected * Get the study drug injected under the skin of the abdomen, thigh, or elsewhere on the body. They will be watched for at least 2 hours. Participants will be instructed on tracking how they are feeling and any side effects. Participants will have 4 more visits over 40 weeks. They will get the study drug and repeat the baseline tests. Participants may have up to 5 more tissue biopsies. Participants will be called between visits to discuss how they are feeling and side effects. Participants will have a final visit 52 weeks after the baseline. They will repeat most of the baseline tests. Participants will answer questions about their oral ulcers.

Lymphocyte adhesion deficiency type 1 (LAD1) is an autosomal recessive disorder of leukocyte function. Decreased expression of the \<=2 subunit of leukocyte integrins results in abnormal cell-cell and cell extracellular matrix adhesion. This disease is characterized by recurrent bacterial infections, impaired wound formation, and other aberrations of adhesion-dependent functions. The severe phenotype can be fatal, but patients with even moderate phenotypes are prone to infection and lose their teeth despite treatment. Ustekinumab is a monoclonal antibody directed against the p40 subunit of human interleukins IL-12 and IL-23. It is approved for treatment of moderate-to-severe plaque psoriasis, active psoriatic arthritis, and moderate-to-severe Crohn s disease. By binding the shared p40 subunit of IL-12 and IL-23, ustekinumab exerts clinical effects through interruption of the TH1 and TH17 cytokine pathways. Previous work at the NIH suggests that blockade of IL-17, which is highly expressed in the gingiva of people with LAD1, can reduce bacterial load and resolve inflammatory gingival disease. We have treated one patient with ustekinumab for 1 year; during this time, he had no serious infections and there was a dramatic resolution of his inflammatory lesions. Our goal is to explore the potential of ustekinumab as treatment for LAD1 inflammatory disease. The objective of this open-label, proof-of-concept study is to evaluate the safety and tolerability of ustekinumab in 10 patients with LAD1. Participants will receive 5 doses of ustekinumab via subcutaneous injection over the course of 1 year. They will be evaluated for adverse events, as well as the effect of the drug on inflammatory lesions and biomarker expression.