Early Detection of Alzheimer's Disease-Related Pathology Using a Multi-Disease Diagnostic Platform Employing Autoantibodies as Blood-Based Biomarkers.

Background: Evidence for the universal presence of IgG autoantibodies in blood and their potential utility for the diagnosis of Alzheimer's disease (AD) and other neurodegenerative diseases has been extensively demonstrated by our laboratory. The fact that AD-related neuropathological changes in the brain can begin more than a decade before tell-tale symptoms emerge has made it difficult to develop diagnostic tests useful for detecting the earliest stages of AD pathogenesis.

Objective: To determine the utility of a panel of autoantibodies for detecting the presence of AD-related pathology along the early AD continuum, including at pre-symptomatic [an average of 4 years before the transition to mild cognitive impairment (MCI)/AD)], prodromal AD (MCI), and mild-moderate AD stages.

Leukotoxin (LtxA; Leukothera): Mechanisms of Action and Therapeutic Applications.

is an oral pathogen that produces the RTX toxin, leukotoxin (LtxA; Leukothera). is strongly associated with the development of localized aggressive periodontitis. LtxA acts as a virulence factor for to subvert the host immune response by binding to the β integrin lymphocyte function-associated antigen-1 (LFA-1; CD11a/CD18) on white blood cells (WBCs), causing cell death.

Aggregatibacter actinomycetemcomitans Leukotoxin (LtxA) Requires Death Receptor Fas, in Addition to LFA-1, To Trigger Cell Death in T Lymphocytes.

Leukotoxin (LtxA) (trade name, Leukothera) is a protein secreted by the oral bacterium is an oral pathogen strongly associated with development of localized aggressive periodontitis. LtxA acts as a virulence factor for by binding to the β integrin lymphocyte function-associated antigen-1 (LFA-1; CD11a/CD18) on white blood cells (WBCs) and causing cell death. In addition, because of its specificity for malignant and activated WBCs, LtxA is being investigated as a therapeutic agent for treatment of hematological malignancies and autoimmune diseases.

Autoantibodies as diagnostic biomarkers for the detection and subtyping of multiple sclerosis.

The goal of this preliminary proof-of-concept study was to use human protein microarrays to identify blood-based autoantibody biomarkers capable of diagnosing multiple sclerosis (MS). Using sera from 112 subjects, including 51 MS subjects, autoantibody biomarkers effectively differentiated MS subjects from age- and gender-matched normal and breast cancer controls with 95.0% and 100% overall accuracy, but not from subjects with Parkinson's disease.

Detection of Alzheimer's disease at mild cognitive impairment and disease progression using autoantibodies as blood-based biomarkers.

Introduction: There is an urgent need to identify biomarkers that can accurately detect and diagnose Alzheimer's disease (AD). Autoantibodies are abundant and ubiquitous in human sera and have been previously demonstrated as disease-specific biomarkers capable of accurately diagnosing mild-moderate stages of AD and Parkinson's disease.

Methods: Sera from 236 subjects, including 50 mild cognitive impairment (MCI) subjects with confirmed low CSF Aβ42 levels, were screened with human protein microarrays to identify potential biomarkers for MCI.

Potential utility of autoantibodies as blood-based biomarkers for early detection and diagnosis of Parkinson's disease.

Introduction: There is a great need to identify readily accessible, blood-based biomarkers for Parkinson's disease (PD) that are useful for accurate early detection and diagnosis. This advancement would allow early patient treatment and enrollment into clinical trials, both of which would greatly facilitate the development of new therapies for PD.

Methods: Sera from a total of 398 subjects, including 103 early-stage PD subjects derived from the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) study, were screened with human protein microarrays containing 9,486 potential antigen targets to identify autoantibodies potentially useful as biomarkers for PD.

LFA-1-targeting Leukotoxin (LtxA; Leukothera®) causes lymphoma tumor regression in a humanized mouse model and requires caspase-8 and Fas to kill malignant lymphocytes.

Leukotoxin (LtxA) is a protein secreted from the oral bacterium Aggregatibacter actinomycetemcomitans. LtxA binds to the β2 integrin lymphocyte-associated function antigen-1 (LFA-1) on human white blood cells (WBCs), resulting in cell death. LtxA is currently under investigation as a novel therapy (Leukothera(®)) for treating hematologic malignancies and autoimmune diseases.

Diagnosis of Alzheimer's disease based on disease-specific autoantibody profiles in human sera.

After decades of Alzheimer's disease (AD) research, the development of a definitive diagnostic test for this disease has remained elusive. The discovery of blood-borne biomarkers yielding an accurate and relatively non-invasive test has been a primary goal. Using human protein microarrays to characterize the differential expression of serum autoantibodies in AD and non-demented control (NDC) groups, we identified potential diagnostic biomarkers for AD.

In vitro synergism between LFA-1 targeting leukotoxin (Leukothera™) and standard chemotherapeutic agents in leukemia cells.

Leukotoxin (Leukothera™; LtxA) is a bacterial protein and experimental therapeutic that binds leukocyte function antigen (LFA-1) on white blood cells (WBCs) and induces cell death via apoptosis or necrosis. We previously found that LtxA preferentially targets WBCs with high levels of activated LFA-1, which is characteristic of many leukemias and lymphomas, and showed that LtxA exhibits significant anti-leukemia activity in vivo using the humanized SCID mouse model. In this report, we demonstrate that LtxA induces very rapid (1h) apoptosis in acute monocytic leukemia THP-1 cells characterized by binding of annexin V to cells, loss of mitochondrial membrane potential, depletion of cellular ATP, and fragmentation of chromosomal DNA.

Resolution of psoriasis by a leukocyte-targeting bacterial protein in a humanized mouse model.

Psoriasis is a very common chronic skin disease, affecting 2-3% of the world's population or more than 125 million individuals worldwide. The characteristic lesion of psoriasis is due to rapid proliferation and shortened transition of keratinocytes through the epidermis. Proinflammatory white blood cells (WBCs) migrate into the psoriatic plaques, and the pathogenic cytokine environment causes the changes in keratinocyte proliferation and differentiation.

Prodrug of proline analogue reduces hypoxic pulmonary hypertension in rats.

A polymeric prodrug of the proline analogue cis-4-hydroxy-l-proline (CHOP), poly(ethylene glycol)-lysine-CHOP or CHOP-PEG, prevents hypoxic pulmonary hypertension in rats by inhibiting collagen accumulation. A more potent prodrug was synthesized by increasing the loading of CHOP on the carrier from 14 to 100%. Pulmonary antihypertensive efficacy and pharmacokinetics are described in the rat hypoxia model.