SBIR-STTR Award

Cerebral Amyloid Angiopathy (CAA) is an age associated disease in which amyloid deposits form in the blood vessel walls of the central nervous system. CAA is a major cause of spontaneous intracerebral haemorrhage in elderly people and an important contributor to age- related cognitive decline. Diagnosis is often missed by physicians as the presenting symptoms are similar to those of a stroke and can be further complicated as CAA is found in most Alzheimer’s disease patients. Current diagnosis of CAA involves expensive and invasive procedures such as an MRI and brain biopsy. A critical goal in the field is to reliably identify CAA at the early, asymptomatic stages of the disease, to allow the best chance for correct disease modifying or preventive treatments to be effective. This proposal aims to develop small molecule fluorescent probe as a novel diagnostic CAA.

Public Health Relevance Statement:
Project Narrative Cerebral Amyloid Angiopathy (CAA) is an age associated disease in which amyloid deposits form in the blood vessel walls of the central nervous system. Recently, these amyloids have been identified in retinal tissue in diseased individuals. The proposed research aims to advance a diagnostic to image amyloid-deposits associated with through the eye.

Project Terms:
Age; Age-associated memory impairment; Alzheimer's Disease; Amyloid; Amyloid beta-Protein; amyloid imaging; Amyloid Proteins; Animal Model; Autopsy; Binding; Biopsy; Blood Vessels; Brain; Cerebral Amyloid Angiopathy; Cerebral hemisphere hemorrhage; Cerebrum; clinical application; Color; Communities; companion diagnostics; Dementia; Deposition; design; Detection; Development; Diagnosis; Diagnostic; Disease; disease diagnosis; Early Diagnosis; Elderly; Evaluation; experimental study; Eye; Family; Fluorescence; Fluorescent Probes; fluorophore; Formulation; Goals; Grant; Histopathology; Human; Image; in vivo; Individual; innovation; Institutes; instrumentation; intraperitoneal; Lead; Learning; Magnetic Resonance Imaging; Medical; Methods; misfolded protein; Modeling; Monitor; mouse model; Neuraxis; novel; novel diagnostics; novel strategies; novel therapeutics; Ophthalmic examination and evaluation; Patient Care; Patients; Peptides; Pharmacologic Substance; Phase; Physicians; Pilot Projects; Preventive treatment; Prions; Procedures; Property; Reporting; Research; Retinal; Sampling; screening; small molecule; Staining method; Stains; standard care; stroke; Symptoms; Terminal Disease; Testing; Tissues; tool; Transgenic Animals; Transgenic Mice; Translating; Work

Cerebral amyloid angiopathy (CAA) is a common neuropathological finding among older adults and is characterized by amyloid beta (A?) deposits in blood vessel walls of the brain. CAA is a major cause of spontaneous intracerebral hemorrhage and an important contributor to age related cognitive decline. Diagnosis is often missed by physicians as the presenting symptoms are similar to a stroke and can be further complicated as CAA is found in over 80% of Alzheimer’s disease patients. Standard diagnosis of probable CAA involves expensive imaging techniques and an invasive brain biopsy. The only definitive way to diagnose CAA is through post-mortem analysis. An ante-mortem diagnostic is needed that can reliably identify CAA at the early, asymptomatic stages, enabling a correct diagnosis to avoid medications contraindicated in the disease. Furthermore, a useful and affordable outcome marker is needed for clinical trials focused on therapies for CAA that could stop or reverse progression of the disease. Amydis aims to address these unmet needs by identifying A? in the eye, as a window to the brain, for early detection of CAA. Several amyloid forming peptides can lead to CAA, among them, amyloid beta (1-40), A?40, is by far the most prevalent form. Amydis’ probes have demonstrated significant fluorescence enhancement in vitro with synthetically aggregated A?40, the ability to detect retinal amyloid deposits in vivo in transgenic mouse models, and detection of amyloid deposits ex vivo with human brain tissue from CAA patients. We have selected our lead clinical candidate, AMDX- 2011P, based on properties amenable for commercial development. With this proposal we aim to 1) develop a chemical synthesis and formulation of AMDX-2011P in preparation for clinical trials, 2) complete preclinical studies to assess the metabolism, pharmacokinetics and toxicity of AMDX- 2011P and 3) complete investigational new drug (IND) enabling studies to file an IND with the FDA. Completion of these aims will advance the development of our in vivo ocular diagnostic test into human clinical trials, getting us one step closer to our mission of providing an ante-mortem, simple and affordable CAA diagnostic.

Public Health Relevance Statement:
Project Narrative Cerebral Amyloid Angiopathy (CAA) is an age-associated disease where amyloid builds up on the walls of the arteries in the brain, increasing the risk for stroke. Retinal abnormalities have been reported in patients that mirror the known histopathology of CAA in cerebral vessels. The proposed research aims to advance an ocular ante-mortem diagnostic test for CAA.

NIH Spending Category:
Acquired Cognitive Impairment; Aging; Alzheimer's Disease; Alzheimer's Disease Related Dementias (ADRD); Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD); Brain Disorders; Cerebrovascular; Dementia; Eye Disease and Disorders of Vision; Neurodegenerative; Neurosciences; Orphan Drug; Rare Diseases; Stroke; Vascular Cognitive Impairment/Dementia

Project Terms:
Address; Advanced Development; Age; Age-associated memory impairment; Alzheimer's Disease; Amyloid; Amyloid beta-Protein; Amyloidosis; Animal Model; Arteries; Autopsy; base; Binding; Biological Markers; Biopsy; Blood Vessels; Brain; Brain hemorrhage; brain tissue; Canis familiaris; Caring; Cerebral Amyloid Angiopathy; Cerebral hemisphere hemorrhage; Cerebrum; chemical synthesis; Chemistry; Clinic; Clinical; clinical candidate; Clinical Research; Clinical Trials; Deposition; design; Detection; Development; Diagnosis; diagnosis standard; Diagnostic; Diagnostic tests; Disease; Disease Progression; Dose; Drug Kinetics; Early Diagnosis; Elderly; experimental study; Eye; Fluorescence; Fluorescent Probes; Formulation; genotoxicity; Goals; Hand; healthy volunteer; Histopathology; Human; Imaging Techniques; improved; In Vitro; in vivo; innovation; inorganic phosphate; Investigational Drugs; Lead; Legal patent; Libraries; Magnetic Resonance Imaging; meetings; metabolic abnormality assessment; Metabolism; Mission; Monitor; mouse model; Neuraxis; Neurologist; novel; off-patent; One-Step dentin bonding system; Outcome; Patient Care; Patients; Peptides; Pharmaceutical Preparations; Pharmacology; Phase; Physicians; preclinical study; Preparation; Procedures; Process; Prodrugs; Property; Rattus; Reporting; Research; Retina; Retinal; Risk; Safety; small molecule; Specialist; standard care; standard of care; Stroke; stroke risk; Symptoms; Technology; Testing; Tissues; tool; Toxic effect; Transgenic Mice; Validation; Work