LIFESENSORS, INC. — Department of Health and Human Services SBIR Phase II: NIA

Description

While sensitive imaging tools to detectamyloid and tau proteins and other biomarkers for established Alzheimer s diseaseADand other neurodegenerative diseases are availablesimilar tools for detecting presymptomaticetiologic biomarkers of these diseases are notAmong the earliest steps in AD is a failure of the ubiquitin proteasome pathway to respond to misfolded proteins by causing their degradationthereby promoting aggregationThis early pathological event is marked in part by changes in protein ubiquitylation patterns in neuronal cellsUbiquitylation patternsencompasses multiple ubiquitin chains and lysine positionsand this information is far more complex than a simple ubiquitylation eventIn additionubiquitylation patterns in neuronal cells of AD patients change as the disease progressesNo non invasive blood test for pre symptoms or etiology of Alzheimers disease has been approved by the FDAIn addition to diagnosisthe ability to identify molecular signatures of AD could help stratify the patient populationand changes in ubiquitylation patterns could be used to monitor the clinical efficacy of drugs that target the ubiquitin proteasome systemThe aim of this project is to capture the initial step in neurodegenerative disease establishment as well as stages in disease progression by identifying appropriate ubiquitylation pattern signatures that can be detected routinely in a diagnostic assayToward this endin Phase ILifeSensors developed a highly sensitive method to isolate poly ubiquitylated proteins based on Ub chain selectivity using TUBESan affinity matrix that can bind selectively to various distinct poly Ub chainsin concert with mass spectrometryMSto identify molecular signatures based on ubiquitylationConditions were simulated in neuronal cells that mimic neurodegenerationand marker proteins were identifiedin additionmethods were developed to identify low levels of ubiquitylated proteins and observe changes in ubiquitylation patterns from cerebrospinal fluidCSFof normal and AD patientsIn Phase IIit is proposed to extend these studies to examine CSF and serum ubiquitylated protein molecular signatures from approximatelynormal and AD patientsLifeSensors will collaborate with DrsNicholas Seyfried and Allan Levey of the Alzheimer s Disease Research Centerleaders in AD proteomicsto translate the tools developed in Phase I to monitor ubiquitylation pattern changes in CSF of normal controls and AD patients and to establish biomarker panels that distinguish controls from AD patients at various disease stagesvalidating the markers using existing databases and predictive studiesSuccess in Phase II will lead to the discovery of novel ubiquitylation signatures for various stages of ADLifeSensors will commercialize stable isotope labeled versions of these proteins to quantify the markers by mass spec in the serum and or CSFThese simple tests will stratify patient populations to monitor efficacy in clinical trials and guide the choice and dosage of drug to treat AD Selective biomarkers for detecting pre symptomatic neurodegenerative diseases such as Alzheimer s disease are currently not availablethe ability to establish such molecular signatures of the disease at various stages would aid in both diagnosis and treatment monitoringLifesensors has identified several proteins whose tagging with ubiquitin is specific for Alzheimer patientsand they will develop this finding into a quantitative assay to facilitate diagnosis of Alzheimer s disease and monitor its progression to guide treatment strategies