Project Abstract
The TTR Amyloidoses (ATTRs) are rare progressive fatal diseases that affect multiple organs, causing
a wide range of debilitating clinical symptoms. ATTRs are caused by the misfolding/aggregation and deposition
of transthyretin (TTR) aggregates with subsequent tissue compromise. Over 100 germ line mutations are
associated with autosomal dominant ATTRs, with varying penetrance and clinical manifestations even in
individuals with the same mutation. ATTR presenting as primary polyneuropathy (FAP) or cardiomyopathy
(FAC) are traditionally diagnosed through clinical observations, Congo red and immunohistochemical staining
of tissue biopsies, with the diagnosis confirmed by genetic testing. Even with emerging technology such as
PET amyloid imaging, lack of accessibility and lack of specificity are still factors making ATTRs widely
underdiagnosed diseases. Recent advances in the development and commercialization of disease modifying
therapeutics targeting ATTRs further underline the need for early and specific diagnosis. It is clear that early
detection and treatment of the TTR amyloidoses and other amyloid diseases, notably light chain amyloidosis,
lead to a superior clinical outcome. In addition to early diagnosis and patient identification, drug development
programs targeting ATTRs will greatly benefit from incorporating an objective biomarker that can monitor drug
response or serve as a validated surrogate endpoint for regulatory agency assessment.
Misfolding and aggregation of mutant TTR presumably occurs from the time of conception and
continues for years before amyloid formation is detected and symptoms emerge. These distinctive non-native
protein structures are believed to be the proximal pathogenetic molecules producing tissue damage. Reduction
of the pathologically related species is a necessary step in achieving a favorable clinical outcome, regardless
of therapeutic modality. Hence these non-native protein structures are ideal biomarkers for early patient
identification, and as indicators of response to treatment. We have developed an immunoassay (NNTTR-Dx)
using proprietary antibodies specific for misfolded forms of TTR. We have shown that the NNTTR-Dx assay
can rapidly and accurately identify V30M and other ATTR polyneuropathy patients. It has also been used to
demonstrate quantitative reduction of non-native forms of TTR in plasma samples of patients receiving
different classes of ATTR therapeutics. Herein, we propose to further develop the antibodies/assay and to
cover additional ATTR mutations associated with other disease phenotypes. A successful outcome of this
proposal will be a rapid diagnostic test that can specifically identify all ATTR patients and monitor their
response to therapeutics. If we are successful, further development will be pursued in a phase II SBIR
proposal.
