Objective:
This program seeks to advance the development of high-performance, quantitative alpha-synuclein seed amplification assays (aSyn-SAAs), addressing the critical need for less invasive, highly sensitive and quantitative biomarkers in Parkinson’s disease (PD) clinical trials.
Research must address one or both critical gaps to integrate aSyn-SAA into clinical practice and therapeutic development:
- Current aSyn-SAAs provide binary (positive/negative) results rather than quantitative assessment, precluding their use for monitoring disease progression and evaluating treatment effects.
- The invasiveness of spinal tap limits its utility in routine clinical practice, can delay or deter subject recruitment in clinical trials, has poor accessibility/acceptance in some geographies and is not amendable to request repeated sampling.
Research must aim to overcome these challenges through the development of quantitative aSyn-SAA in cerebral spinal fluid (CSF) and in less invasive methods around biofluids or tissue.
MJFF’s priorities for this Request for Applications are aligned with the current state of the field as described below:
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Existing aSyn-SAA in CSF exhibits extremely high sensitivity and specificity for neuronal synuclein disease and can identify individuals who are at high risk for developing PD and Dementia with Lewy Bodies (DLB) years before symptom onset. Nonetheless, CSF-SAA cannot be used as a biomarker of disease progression or pharmacodynamic/therapeutic response without technical advances that enable robust quantitation. Proposals addressing this critical need that can advance the quantitation of SAA in any biological matrix (including CSF) will be given top priority.
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aSyn-SAA in other biofluids and tissues have the potential to augment CSF assays but require further analytical development and validation. While studies have demonstrated feasibility in matrices such as skin, blood, tears, saliva and olfactory mucosa, the field still grapples with issues of sensitivity, specificity and reproducibility. Pre-analytical variables, such as optimal methods for sample collection, storage and processing are poorly understood and vary between studies. These gaps in standardization hinder scalability and clinical applicability of SAA in peripheral matrices, making it critical to address these challenges to fully realize the potential of these less-invasive matrices. SAAs in peripheral matrices are also not yet quantitative.
MJFF will prioritize proposals that:
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Develop high-performance, quantitative seed amplification assays for alpha-synuclein.
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Tackle challenges in sensitivity, specificity and reproducibility of SAA in peripheral biofluids and tissues.
MJFF will NOT consider proposals focused on:
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CSF SAA that is strictly binary.
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Semi-quantitative SAA in CSF that is based on the analysis of serial endpoint dilutions.
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Immunoassays to measure post-translationally modified forms of aSyn (e.g. pS129-aSyn) or ‘total’ aSyn.
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Other non-SAA techniques.
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aSyn imaging proposals.
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SAA for misfolded proteins other than aSyn – Please note that although SAA for other proteins such as TDP-43 and tau are out of scope for this program, you may reach out to us at grants@michaejfox.org to discuss future opportunities.
If your proposal is out of scope, you are not guaranteed feedback.
For general questions about the application process, please email grants@michaeljfox.org.