DAY TWO
8:00 am Morning Coffee & Light Breakfast
8:50 am Chair’s Opening Remarks
Advancing Specific & Efficacious Small Molecules Targeting RNA for Treating Neurological Disorders to Help the Patients in Need
9:00 am Developing RNA-Modulating Oral Small Molecules Targeting PMS1 to Treat Incurable Neurological Disorders
Synopsis
- Leveraging our proprietary, integrative RNA-targeting small molecule discovery platform to pioneer the development of first-in-class oral therapies
- Pursuing oncology and neurological disease targets, exemplified by the oncogenic transcription factor target c-MYB and the PMS1 gene
- PMS1 is a key component of the DNA mismatch repair pathway, implicated in the pathological somatic trinucleotide repeat expansion observed in Huntington's Disease (HD) and other trinucleotide repeat expansion disorders
9:30 am PTC518 Mediated Splice-Induced HTT Lowering: Pathway from Concept to Patients
Synopsis
- Uncovering how animal models demonstrated that reducing mutant huntingtin protein (mHTT) levels could alleviate Huntington’s disease (HD)-like symptoms
- Reviewing the discovery and development of PTC518, a small molecule splicing modifier that reduces the production of the mHTT protein in cells and animals
- Highlighting PTC518’s clinical data to demonstrate proof of mechanism and dose-dependent lowering of HTT mRNA and protein levels in healthy volunteers and HD patients
10:00 am Multidimensional Profiling & Validation of Small Molecule Targets
Synopsis
- Discover multiomic approaches for target discovery and validation
- Identify disease-specific, druggable pockets
- Validate small molecule binding to target RNAs
10:10 am Morning Break & Networking
Unravelling the Biology of Splicing to Advance Small Molecule Modulators & Identify Novel Splice Sites to Widen the Landscape of Treatable Diseases
11:00 am Splicing: Predictive Models & Variability Between People
Synopsis
- KATMAP learns a regulatory activity map for splicing factors using knockdown and in vitro RNA-binding data
- Direct regulatory target exons and associated regulatory elements are predicted
- Using GTEx RNA-seq data, we have identified tens of thousands of “naturally variable exons” (NVEs) that are spliced in some people but not others and shown that NVEs aid in interpretation of genetic variants
11:30 am Showcasing Insights to A-bulge Splice Modulator Selectivity Derived from Studies of Minigenes & Other Genetic Instruments
Synopsis
- Uncovering effects of splice site modification on splice modulator activity
- Delving into transcriptomic comparisons of different splice modulator modalities to identify selective compounds
- Deep diving into highly-specific splice modulator discovery to advance development of small molecules
12:00 pm Identifying Small Molecules Targeting Novel Splice Sites Leading to Therapeutic Effect
Synopsis
- Implementation of PTSeekTM to discover novel small molecules that target splice sites found in intron-derived exons of therapeutically relevant targets
- Advancement of splicing modifiers to treat human diseases of unmet medical need
12:30 pm Unlocking the Therapeutic Potential of Small Molecule mRNA Splicing Modulators to Prevent Somatic Expansion in Huntington’s Disease
Synopsis
- Exploring the molecular mechanisms by which small molecule mRNA splicing modulators interact with the mismatch repair (MMR) pathway to prevent somatic expansion
- Summarizing results from in vivo studies that evaluate the therapeutic potential of small molecule mRNA splicing modulators to address somatic expansion
- Highlighting key findings that show the impact on the mismatch repair pathway, including changes in gene expression, protein levels, and cellular phenotypes relevant to Huntington's Disease
1:00 pm Lunch Break & Networking
Unlocking Small Molecule’s Potential in the RNA-Targeting Field to Increase Investment & Treatment of a Wider Portfolio of Disease
2:00 pm Panel Discussion: Discussing Investment in RNA-Targeting Therapeutics to Accelerate Advancement of Small Molecule Therapies for Patients in Need
Synopsis
- What motivation do venture capitalists need to invest in RNA targeting small molecule therapeutics?
- What do venture capitalists view as critical points of investment both in preclinical and early clinical development?
- What do investors look for in investable ideas and approaches within the RNA-targeting field?
3:00 pm Afternoon Break & Networking
Optimizing Small Molecule Design for Greater Selectivity & Binding Affinity to Advance More Effective RNA Targeting Therapeutics & Imaging Agents
3:30 pm Small Molecules Modulate Stability of MALAT1 Substructures
Synopsis
- RNA-targeted libraries yield small molecule modulators of RNA conformation and function
- Oncogenic MALAT1 lncRNA contains ligandable substructures with putative function
- Tunable small molecules modulate MALAT1: protein interactions and lead to rapid degradation
4:00 pm Structure- & Fragment- Based Design of Small Molecule RNA Imaging Agents
Synopsis
- Fluorogenic RNA aptamers are powerful tools to image RNA in live cells
- Broad adaptation of this technology requires new, brighter fluorophore systems
- Structure- and fragment- based design enables the discovery of an ultrabright RNA activated fluorophore