CURE SYNGAP1 (fka SynGAP Research Fund) has seven scientific programs for grant funding. These programs cover many of the steps required to develop disease modifying treatments. Understanding the mechanism of disease and creating gene-specific therapeutics are just the beginning. We also fund projects that find existing drugs to alleviate symptoms and create patient-relevant disease models. We prepare for clinical trials with investments in measures of SYNGAP1-Related Disorders (SRD) that correlate with meaningful outcomes of health, and collect data on the progression of the disease under the current standard of care.
Many steps are required to create and make available gene-specific medicines. CURE SYNGAP1 keeps track of investment in the steps with seven grant-funding programs.
BTS – Basic and Translational Science
The Basic and Translational Science (BTS) program holds the projects that define the specific problems in SRD and build specific treatments. The work here is foundational, and the time scale for these projects is multiple years. Basic science reveals what goes wrong in tissues and cells when a SYNGAP1 gene is broken. Translational Science uses learnings from basic science to design new types of medicines, and includes preclinical testing of new drugs and methodologies.
PURPOSE – Drug repurposing
Drug Repurposing can be much faster and cheaper than creating novel precision medicines. The strategy is to find existing drugs to improve symptoms of a disorder. The PURPOSE program encompasses all aspects of drug repurposing, from drug screening, assessment of drug hits, building and running decentralized observational trials, and preclinical basic science on the drugs that show promise.
SMART – SYNGAP1 Missense Analysis, Research, & Therapeutics
In SRD, approximately 13% of the pathogenic variants create a full length protein with a single amino acid change (missense variants). Unlike Protein Truncating Variants (PTVs, 80%+ of the variants), each new missense variant has the potential to have a different consequence on the biochemistry and biology of the protein, so should be assessed individually. The SYNGAP1 Missense Analysis, Research, and Therapeutics program targets three types of projects: determining the consequence and disease model for missense variants; finding more patients by resolving the categorization of Variants of Uncertain Significance (VUS) into pathogenic and benign; developing and testing therapeutics for missense variants found in patients.
While all the CURE SYNGAP1 programs include missense variants, not all therapeutics will work on all disease models. So it is incumbent upon us to investigate the categorization of all SYNGAP1 VUS and to investigate the disease model for all missense variants. In fact, the understanding of missense variants will lead to a richer, more nuanced understanding of SYNGAP1 functions and protein-protein interactions than studying haploinsufficiency only.
SBOM – SYNGAP1 Biomarkers & Endpoints
All therapeutics, whether they come from the BTS, PURPOSE, or SMART program, need to show efficacy to be available to patients. The SYNGAP1 Biomarkers and Endpoints program invests in methods to discover, create and validate measures for use in clinical trials. Treatment efficacy is shown by seeing a measurable change that correlates with a meaningful outcome of health.
Endpoints are the specific measurable changes chosen for Clinical Trials. Biomarkers and clinical measures are changes that can be tabulated and correlate with a meaningful aspect of disease. Biomarkers include detection of molecules or other biological phenomena (e.g. a protein or RNA level in blood or CSF, signal in EEGs or actigraphy data). Clinical measures and Patient- and Caregiver-Reported Outcomes measure changes that can be observed. While we focus on developing biomarkers for treatment efficacy, other uses include diagnostics, treatment progression, subtype delineation, and more.
Facilitate – Patient-relevant Research Tools and Reagents
To ensure and encourage patient-relevant research in BTS, we prioritize the creation and phenotyping of disease models that reflect variants found in SRD patients. We also collect, test, distribute, and encourage use of patient biosamples and iPSC lines from patients, and other research assets. The Facilitate program keeps track of spending in this category.
SRDC – SYNGAP1-Related Disorders Characterization – A long-term, rich characterization of SRD is essential for successful clinical trials and for improved clinical care of our patients. SRDC focuses on characterizing the breadth and depth of the disorder and improved clinical care for improved outcomes.
SYNGAP1 ProMMiS – Prospective Multidisciplinary, Multisite Study
Clinical trials for ultra rare disorders like SRD rely on the data from a comprehensive Natural History Study to choose measures and endpoints, and to reduce the need for a placebo arm. SYNGAP1 ProMMiS is designed to support Clinical Trial readiness by collecting clinical data every 6 months for multiple years, and by showing that the same data can be collected at multiple sites.
The seven grant funding programs are supported by extensive collaboration, including attending conferences, holding virtual topic-specific summits, webinars, and our annual CURE SYNGAP1 Science Conference.