The transthyretin (TTR) Amyloidoses (ATTR) are progressive fatal diseases caused by the misfolding, aggregation and deposition of mutant and wild-type forms of TTR, a homotetrameric thyroxin transporting protein secreted by the liver, choroid plexus and retina. ATTR presenting as primary polyneuropathy (FAP) can affect the peripheral, autonomic and central nervous systems (CNS). It is traditionally diagnosed by clinical observation, Congo red staining of tissue biopsies, coupled with genetic testing. ATTR-FAP is widely underdiagnosed. ATTR-FAP patients commonly have a 2-3-year gap between first symptoms and diagnosis. ATTR affecting the CNS is difficult to diagnose and is often ignored or misdiagnosed. Recent advances in the development and commercialization of disease modifying therapeutics targeting ATTR underline the need for early and specific diagnosis. It is clear from current studies that early detection and treatment of ATTR and other amyloid diseases leads to superior clinical outcomes, as measured by arrest of disease progression and improved quality of life. As much desirable as is to treat the mutations, in practice, it is imperative to implement a objective initiation point for early treatment. Clinical trials targeting ATTR-FAP have employed relatively coarse clinical measures of peripheral nerve function which change relatively slowly requiring 12-24 months of observation to see measurable efficacy. The drug development process would be significantly shortened by monitoring the level of a pathologically related, quantifiable, pharmacodynamic biomarker. As with the A? aggregation seen in Alzheimer?s disease, misfolding/aggregation of TTR occur years before the emergence of symptoms and detectable amyloid formation. These distinctive circulating non-native TTR (NNTTR) structures are believed to be the proximal pathogenetic molecules producing neurotoxicity and tissue damage, making them ideal candidate biomarkers for early patient identification, and as a pharmaco- dynamic marker to monitor disease progression and drug response. We have developed a sandwich ELISA assay using proprietary antibodies specific for NNTTR. We have shown that the NNTTR immunoassay can rapidly and accurately identify pre-symptomatic carriers and V30M-TTR (most common mutation) and other ATTR-FAP patients using plasma and cerebrospinal fluid (CSF) samples. NNTTR levels are increased in plasma of pre-symptomatic carriers before symptom onset and are reduced in patients receiving different classes of ATTR therapeutics. Herein, we propose to conduct a full analytical validation of the NNTTR candidate biomarker, aiming at developing a robust quantitative measurement of NNTTR. If we are successful, further clinical validation and qualification will be pursued. The resulting NNTTR biomarker/assay can be used as an early diagnostic to specifically identify patients who can benefit from targeted ATTR therapeutics, such as tafamidis, patisiran, and inotersen, as well as additional ATTR therapeutics, currently in development, that may be more effective in the treatment and prevention of CNS disease.

Public Health Relevance

TTR Amyloidoses (ATTR) are rare but progressive fatal diseases that affect multiple organs, causing a wide range of degenerative phenotypes affecting the peripheral, autonomic and central nervous systems. Multiple ATTR targeted therapeutics in clinical development or already on the market will greatly benefit from having a rapid, reliable, and specific early diagnostic. Analytical and subsequent clinical validation of the non-native TTR (NNTTR) biomarker and our proprietary NNTTR immunoassays will enable its clinical utilities and contribute to the clinical decision making and patient management of ATTR.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Small Business Innovation Research (SBIR) Cooperative Agreements - Phase II (U44)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Pelleymounter, Mary A
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Protego Biopharma, Inc.
San Diego
United States
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