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

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 gingival 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.

- No presence of teeth.

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