Project Description
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 Aß 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.
