Development of an early diagnostic and biomarker of treatment response for TTR amyloidoses (ATTR)

Project AbstractThe TTR AmyloidosesATTRsare rare progressive fatal diseases that affect multiple organscausing a wide range of debilitating clinical symptomsATTRs are caused by the misfolding aggregation and deposition of transthyretinTTRaggregates with subsequent tissue compromiseOvergerm line mutations are associated with autosomal dominant ATTRswith varying penetrance and clinical manifestations even in individuals with the same mutationATTR presenting as primary polyneuropathyFAPor cardiomyopathyFACare traditionally diagnosed through clinical observationsCongo red and immunohistochemical staining of tissue biopsieswith the diagnosis confirmed by genetic testingEven with emerging technology such as PET amyloid imaginglack of accessibility and lack of specificity are still factors making ATTRs widely underdiagnosed diseasesRecent advances in the development and commercialization of disease modifying therapeutics targeting ATTRs further underline the need for early and specific diagnosisIt is clear that early detection and treatment of the TTR amyloidoses and other amyloid diseasesnotably light chain amyloidosislead to a superior clinical outcomeIn addition to early diagnosis and patient identificationdrug 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 assessmentMisfolding and aggregation of mutant TTR presumably occurs from the time of conception and continues for years before amyloid formation is detected and symptoms emergeThese distinctive non native protein structures are believed to be the proximal pathogenetic molecules producing tissue damageReduction of the pathologically related species is a necessary step in achieving a favorable clinical outcomeregardless of therapeutic modalityHence these non native protein structures are ideal biomarkers for early patient identificationand as indicators of response to treatmentWe have developed an immunoassayNNTTR Dxusing proprietary antibodies specific for misfolded forms of TTRWe have shown that the NNTTR Dx assay can rapidly and accurately identify VM and other ATTR polyneuropathy patientsIt has also been used to demonstrate quantitative reduction of non native forms of TTR in plasma samples of patients receiving different classes of ATTR therapeuticsHereinwe propose to further develop the antibodies assay and to cover additional ATTR mutations associated with other disease phenotypesA successful outcome of this proposal will be a rapid diagnostic test that can specifically identify all ATTR patients and monitor their response to therapeuticsIf we are successfulfurther development will be pursued in a phase II SBIR proposal Project NarrativeTTR AmyloidosesATTRsare rare but progressive fatal diseases that affect multiple organscausing a wide range of degenerative phenotypes affecting the heartperipheralautonomic and central nervous systemsthe eyeand in some cases the kidneysMultiple ATTR targeted therapeutics in clinical development or already on the market will greatly benefit from having a rapidreliableand specific early diagnostic that can also serve as a response to therapy biomarkerWe will build onand further developour proprietary TTR immunoassays for the diagnosis and prognosis of ATTRs applicable to all the different genotypes and phenotypes