Development of a Blood-based Diagnostic for Early Detection of Transthyretin Amyloidosis

ABSTRACT Transthyretin amyloidosis (ATTR) is a rare, progressive, and ultimately fatal condition characterized by the abnormal extracellular deposition of transthyretin (TTR) protein within the peripheral nerves (ATTR-PN) and/or within the heart (ATTR-CM). There are two types of ATTR: (1) hereditary ATTR (hATTR), where the destabilizing mutation in the TTR-gene is inherited, or (2) ATTRwt, in which people with the wild-type TTR-gene sequence develop the disease sporadically. Recent estimates put the worldwide number of people affected by ATTR at approximately 550,000. However, these patient populations are thought to be significantly underdiagnosed, as there is a lack of rapid and readily available diagnostics. New diagnostics for ATTR disease are needed as confirmation of ATTR is slow, taking up 5 years. Many patients present with symptoms that can be attributed to other conditions, leading to misdiagnosis. Due to this, ATTR is often diagnosed by process of elimination of other diseases and many patients have to see multiple specialists before getting the correct diagnosis, causing a delay in treatment and further amyloid deposition. Given that the life expectancy once diagnosed with ATTR is only 2-10 years, a blood-based diagnostic and biomarker could be used to shift the current paradigm from confirmation of late-stage deposition to a clinical level screen, allowing an individual with suspected risk to receive disease-modifying treatment earlier, reducing mortality, and improving patient quality of life. Furthermore, a diagnostic biomarker will be invaluable in determining the efficacy of drugs for treatments which have been shown to have variable long-terms outcomes for patients. This will allow physicians to guide patients to the most cost effective and appropriate approved drug therapies for their condition. The path from normal TTR to amyloid deposition proceeds through a monomeric intermediate which can be a biomarker of disease risk and progression. The proposed blood-based diagnostic is designed specifically to detect the TTR monomer using novel, ultra-rare antibodies that have been discovered and will be rapid, sensitive, and non-invasive. In Phase 1, initial proof-of-concept data will be generated to show that there is elevated TTR monomers in patients diagnosed with ATTR compared to normal, healthy donors. If successful, this will be the first step towards the commercialization of the first blood-based diagnostic for the disease.