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

 -  Age 12-65 years.

 -  Molecularly and cellularly confirmed LAD1 with inflammatory lesions.

 -  Willing to allow storage of biological samples for future research.

 -  Willing to allow genetic testing of blood samples.

 -  Able to provide informed consent.

 -  Participants who can get pregnant or impregnate a partner must agree to use adequate
 contraception when engaging in sexual activities that can result in pregnancy.
 Adequate contraception must be used consistently starting at screening and lasting
 through the final study visit. Appropriate forms of contraception include the
 following:

 1. Intrauterine device or equivalent.

 2. Hormonal contraceptive (eg, consistent, timely, and continuous use of
 contraceptive pill, patch, ring, implant, or injection) that has reached full
 efficacy before dosing.

 3. A double barrier method (eg, male/female condom, cap, or diaphragm plus
 spermicide).

 4. Be in a stable, long-term monogamous relationship, per assessment of the
 principal investigator (PI), with a partner who does not pose any potential
 pregnancy risk, eg, has undergone a vasectomy at least 6 months before the first
 dose of study agent or is of the same sex as the participant.

 5. Have had a hysterectomy and/or a bilateral tubal ligation or both ovaries
 removed.

 EXCLUSION CRITERIA:

 -  History of malignancy (except for basal cell carcinoma) within the previous 5 years.

 -  Infected with HIV.

 -  Active uncontrolled bacterial, viral, or fungal infection.

 -  Active or chronic viral hepatitis.

 -  Active or latent untreated tuberculosis.

 -  Received Bacillus Calmette-Guerin vaccine within the last year.

 -  Received live attenuated vaccines within 15 weeks before the first dose.

 -  Allergy to any component of the ustekinumab formulation.

 -  Pregnant or breastfeeding.

 -  Any condition that, in the opinion of the investigator, contraindicates participation
 in this study.