Leukocyte adhesion deficiency type I (LAD1) is a rare and often fatal primary immunodeficiency. It is caused by autosomal recessive mutations in the gene ITGB2, which encodes CD18 (the common β2 subunit) of the β2 family of integrin cell adhesion molecules that are specifically expressed on cells of hematopoietic origin like leukocytes. As a result of decreased function of β2 integrins, leukocytes cannot extravasate from the vasculature and patients suffer from severe life threatening and recurrent non-pustular infections of the soft tissue including skin, mucosal membranes, and intestinal track. Hematopoietic stem cell transplantation is curative, but it is not without significant risk. In more moderate forms of the disease, integrin β2 expression is characterized as being between 2 â 30% of normal levels. An intriguing approach to overcoming the adhesion defects found in moderate LAD1 patients would be to directly activate β2 integrins, like αLβ2, so that even low levels of this integrin would be sufficient to support essential leukocyte functions. Scientists at the Texas Heart Institute have developed a library of small molecule compounds that can directly bind and activate integrin cell adhesion receptors including the integrin αLβ2. These compounds are currently licensed to 7 Hills Pharma and are being developed for immuno-oncology (IO) indications as they can stimulate the immune system and synergize with checkpoint blockade therapies like anti-CTLA-4 and anti-PD(L)1. However, there is a clear opportunity to leverage these compounds as a treatment strategy to activate integrins like αLβ2 and directly target the cause of LAD1. In this phase I SBIR proposal, we will test the hypothesis that activation of β2 integrins with small molecule compounds can overcome the adhesion defects seen in leukocytes of LAD1 patients, and in an animal model of moderate LAD1. In proposed aims we will screen over 500 integrin activating compounds, from 5 structural classes, to identify potent β2 integrin activators. Representative compounds from each structural class will then be tested against a panel of mutations identified from moderate LAD1 patients. In vivo proof-of-concept experiments will be performed by testing integrin activating compounds in acute inflammatory responses in the CD18hypo mouse, which mimics moderate LAD1. Lastly, pharmacodynamic models of compound activity will be developed to inform future clinical development. The goal of this drug development program is the development of a safe and effective orally available treatment for patients with moderate to severe LAD1, an orphan disease indication for which there are no effective treatments outside of bone-marrow transplantation.
Public Health Relevance Statement: Leukocyte adhesion deficiency is a rare genetic disease that prevents inflammatory cells from engaging in the first line of defense against bacterial infections. Recurrent and refractory infections lead to significant mortality and morbidity, even in moderate cases. 7 Hills Pharma, LLC, is developing a novel drug-based therapy to directly target the genetic deficiency in this disease.
Project Terms: Acute; adhesion receptor; Adhesions; Adult; Age; Animal Model; Antibiotic Therapy; Antibiotics; Antitumor Response; Bacterial Infections; base; Binding; Biological Assay; Biological Markers; Bone Marrow Transplantation; Caring; Cell Adhesion; Cell Adhesion Molecules; Cells; Childhood; Chronic; clinical development; Clinical Trials; congenital immunodeficiency; CTLA4 gene; Defect; design; Development; Disease; Dose; drug development; drug standard; effective therapy; efficacy study; efficacy testing; experimental study; Family; Future; Genetic; Goals; Heart; Hematopoietic; Hematopoietic Stem Cell Transplantation; Immune; immune checkpoint blockade; Immune system; Immunologics; Immunooncology; Impaired wound healing; In Vitro; in vivo; Infection; Infiltration; Inflammatory; Inflammatory Response; Institutes; Integrin alpha4beta1; Integrins; Intestines; Investigational New Drug Application; ITGB2 gene; Lead; Leukocyte Adhesion Deficiency; Leukocytes; Leukocytosis; Libraries; Life; Membrane; Methods; migration; Modeling; Morbidity - disease rate; mortality; mouse model; Mucous Membrane; Mus; Mutation; novel; novel therapeutics; Oral; Orphan; outcome forecast; Patient Selection; Patients; Periodontitis; pharmacodynamic biomarker; pharmacodynamic model; Pharmacology and Toxicology; Phase; phase 2 study; preclinical development; predictive test; prevent; Program Development; programs; prophylactic; Rare Diseases; rare genetic disorder; Recurrence; Refractory; Reporting; response; Risk; Safety; Scientist; screening; Site; Skin; skin lesion; Small Business Innovation Research Grant; small molecule; small molecule libraries; Soft Tissue Infections; Structure; Testing; Texas; TimeLine; Tooth Loss; treatment strateg
