SBIR-STTR Award

We will develop an electronic technology to detect fibrillar aggregates, which are characteristic of neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Our preliminary results (detection of 100 protein molecules) indicate that the enhanced sensitivity of our technology could enable the detection of the earliest biochemical evidence of a neurodegenerative disease, like Alzheimer's disease. This would allow the non-invasive screening of patients by analyzing bodily fluids for characteristic fibrils and provide a quantitative method for assessing the efficacy of drugs in clinical trials. The technology can readily be extended to a MEMS (microelectronic and mechanical system) based array assay to multiplex the screening of drugs to inhibit fibril formation. The technology will also enable the rapid screening of nested sets of peptides to identify sequences that participate in fibril formation. We have chosen Alzheimer's disease as our model system to develop and test the technology because it is an important biological problem, fibril formation of beta-amyloid variants has been well characterized in vitro and a likely target for therapeutic intervention, the protofibril, has been identified. However, the technology can be used as a general tool for detecting any protein-protein, antibody-protein or drug-protein interaction in a high-throughput system. PROPOSED COMMERCIAL APPLICATIONS: The rapid electronic detection of fibrillar aggregates characteristic of neurodegenerative diseases will allow for the commercial development of tests to screen pre-symptomatic patients for disease, to objectively monitor response to therapy in symptomatic patients and to screen for drugs that block fibril formation or their incorporation into aggregates

We have developed the first practical assay that directly measures the incorporation of beta-amyloid peptides into aggregates. We have multiplexed the technology to enable the screening of hundreds of thousands of drug candidates for their ability to directly inhibit beta- amyloid aggregation. Because the assay is rapid and does not use toxic substances, it can readily be extended to a whole cell assay. Cells that secrete beta-amyloid can be treated with drug candidates that might inhibit upstream elements such as beta- or gamma-secretase. The amount of secreted beta-amyloid would then be quantitated by our proprietary methods. Preliminary experiments performed on CSF from Alzheimer's patients show that the extent of beta-amyloid aggregation, detected by our technology, scaled with the measured degree of dementia and duration of disease, indicating that a clinical diagnostic assay based on this technology is feasible. The ability to quantitatively assess a patient's response to therapy would expedite clinical trials and FDA approval. Although we have optimized our technology for Alzheimer's disease, the assay is modular and is readily adapted to the specific detection of any neurodegenerative disease that is characterized by abnormal protein aggregation. These include, Alzheimer's. Parkinson's, Huntington's, Creutzfeldt Jakob, Lou Gehrig's and Mad Cow disease. PROPOSED COMMERCIAL APPLICATIONS: We have developed the first specific and sensitive high throughput assay that detects abnormal-protein aggregation characteristic of neurodegenerative diseases. The assay is orders of magnitude more sensitive and specific than the state of the art and has been used to identify a new class of structurally related drugs that inhibit early stage beta-amyloid aggregation, characteristic of Alzheimer's disease. These structural determinants can be used by pharmaceutical companies to generate new combinatorial drug libraries focused on early stage AD. The assay is modular so it can be readily adapted for use in assays that target other neurodegenerative diseases. We will use our technology to develop a more sensitive diagnostic for AD