Project Portugal 2030

Summary

AIMS: For advancement of predictive pathophysiology and therapeutic trials, we aimed at validating potential blood biomarkers of pathophysiology for MJD/SCA3 and SCA37 and apply our proprietary miniaturized biosensor technology for their multiplex quantification to be used at the point of care. Together these validated biomarkers will overcome the current limitations, namely the lack of detection/discrimination in early stages when neuronal damage starts in very young subjects who are decades away from ataxia onset. These young carriers of the disease gene mutation, in a very early presymptomatic stage are the ones who could benefit most from the upcoming therapeutic clinical trials. To achieve this, we defined five specific objectives that will be addressed in five TASKs, and five milestones of progress. The specific objectives are: OBJECTIVE 1 Optimize a highly sensitive aptamer-based high-throughput methodology for quantitative detection and validation of potential blood biomarkers for MJD/SCA3 and SCA37. To quantitatively detect the selected protein biomarkers, we will employ a rational design and optimization for aptamer selection against biomarkers. This design is based on (1) computational methods to select aptamers based on structural similarities to selected protein biomarkers, (2) binding affinity, and (3) experimental validation (TASK1, Milestone 1) OBJECTIVE 2 Uncover predictive biomarkers of pathophysiology severity in MJD/SCA3 and SCA37. For sensitive discrimination of pathophysiological neuronal damage in mutation carriers from non-carriers and presymptomatic from symptomatic severity stages, in MJD/SCA3 and SCA37, we aim to uncover protein biomarker levels in blood that discriminate carrier from non-carrier groups and correlate with severity. This validation will be achieved using the high-throughput technology from TASK1 for quantitative detection of selective biomarkers in MJD/SCA3 and SCA37 mutation carrier and control blood (TASK2, Milestone 2). OBJECTIVE 3 For cross-species validation in reproducible genetic and pathological mouse models, we will apply our high-throughput quantitative detection technology, from TASK1, for quantification of the blood levels of the successful biomarkers from TASK2 in transgenic MJD/SCA3 and SCA37 mice at different ages, before and after the time of disease onset, which is known and not variable as in affected individuals, and in age-matched controls (TASK3, Milestone 3). OBJECTIVE 4 Development and validation of a miniaturized aptamer-sensor technology for biomarker profiling at the point-of-care (Predict-chip), in MJD/SCA3 and SCA37. We aim at optimizing a miniaturized biosensor for minimally-invasive and multiplex molecular profiling of MJD/SCA3 and SCA37 based on our proprietary chip technology. Using this technology, we will multiplex quantitative detection in blood of validated biomarkers, from TASK2 and 3, for discrimination of mutation carriers from noncarriers, and stratification of pathophysiological asymptomatic and symptomatic severity, at the point-of-care (TASK4, Milestone 4 and 5). OBJECTIVE 5 Integrate management, dissemination and commercial valorization to fulfil the objectives of this project. We will focus on management and developing a technological exploitation strategy centered around integrating Predict-Chip technology into MJD/SCA3 and SCA37 disease management workflows (TASK5).