Areas of Interest:

• siRNA delivery platforms for systemic and / or local administration
  • Ability to demonstrate dose-dependent, RNAi-mediated gene silencing in vivo with at least a 10-fold margin for severe toxicities
  • Chemical and / or biological components suitable for enhancing cellular uptake, intracellular trafficking, endosomal escape, and cytosolic release of oligonucleotides to improve potency
  • Chemical and / or biological components capable of conferring improved biocompatibility of RNA nanoparticles / formulations
  • Targeting ligands (antibodies, peptides, aptamers, or small molecules) and linkers suitable for direct siRNA conjugation or for nanoparticle, polymer, or liposome delivery
  • Devices for oligonucleotide delivery
• Assays
  • Novel particle size characterization methods
  • Novel colloid surface characterization methods
  • Biochemical assays for Ago / RISC binding and catalytic activity
  • Assays suitable for measuring cellular uptake, intracellular trafficking, endosomal escape, and cytosolic release of oligonucleotides
• siRNA sequence, structure, and modification
  • Novel chemistries for:
    • Improving resistance to enzymatic and chemical degradation in circulation and during cellular uptake and trafficking (ie, within endosomes)
    • Charge neutralization of siRNA while retaining intrinsic RNAi activity
    • Reducing immunostimulation
    • Enhancing Ago2 / RISC incorporation and potency
    • Oligo modifications that confer increased endosomal escape
    • Improving target specificity
  • Predictive bioinformatic and molecular models
  • Crystallization capabilities for Ago 2
• miRNA
  • Novel chemistries to create miRNA mimics and / or antagonists
  • Assays for pharmacodynamic evaluation of miRNA activity
  • Potential therapeutic agents that:
    • Reduce miRNA levels in animals and generate the expected phenotypic effects
    • Mimic natural miRNA, reduce mRNA levels, and have the expected phenotypic effects
• RNA manufacturing
  • Advancements in large-scale production of modified siRNA
  • Improved processes for increased quality, efficiency, and reduced COG
  • Novel chemistries
  • Universal linker-based solid support for production of siRNAs
  • Robust LC-MS method for determination of impurity profile of phosphoramidite raw materials and oligonucleotides (siRNAs)
  • Alternative methods to produce siRNA clinical supplies
• AAV production
  • High-titer, high-volume AAV production for non-clinical applications and POC

Not Interested in:

• Plasmid DNA-based methods for RNA therapies
• Viral delivery methods for RNA therapies

Areas of Interest:

• Oral delivery technologies:
  • Technologies for delivery of water-insoluble compounds (especially mitigation of food effect)
  • Oral-controlled release technologies to modify pharmacokinetics (eg, increase C_max, AUC, and / or T_1/2 , reduce peak-to-trough ratio):
    • For poorly soluble compounds (<0.1 mg / mL)
    • For compounds with narrow absorption windows (eg, those with poor colonic absorption)
  • Ingredients or formulations that can enhance permeability
  • Orally disintegrating tablet (ODT) technology or film technology with robust in vivo performance and simple packaging
  • Sublingual delivery for fast onset
  • Technologies that protect actives from the GI environment (eg, gastric acid or GI metabolism)
  • Novel oral protein / peptide delivery systems (eg, insulin)
  • Novel solubilizing excipients with accompanying toxicology package for safety assessment studies
• Inhalation / nasal delivery:
  • Delivery systems for small and large molecules
  • Novel in situ modeling (eg, lung solubility or IVIVC)
• Injectable delivery, alternative routes of administration:
  • Injection devices (eg, novel and easy to use self-injection systems, improved liquid / dry reconstitution technologies)
  • Infusion systems (IV and subcutaneous delivery that facilitate hospital and home infusion therapies)
  • Novel skin-based delivery technologies for high concentration antibody formulations and large volumes of liquid (>2 mL)
  • Technologies for delivery of water-insoluble compounds (eg, IV-administered nanosuspensions or dispersed systems for small molecules and peptides)
  • Systems (including implants) for sustained release of small and large molecules from one week to several months, up to years (long-acting implants)
  • Vaginal ring and intrauterine delivery
• Back-of-the-eye delivery systems (eg, invasive and noninvasive, clinically proven technologies for retinal delivery of small molecules, siRNA* and trophic factors)
• Novel passive and active (eg, microneedles) transdermal and topical technologies for small molecule and peptide delivery
  • Technologies that enable delivery of higher (>20 mg) doses
• Intelligent delivery systems capable of modulated delivery (eg, signal or drug concentration); personalized / feedback control

* See RNA Therapeutics section for complete listing of interests related to delivery of nucleic acids.

Areas of Interest:

• In vivo platforms that replicate human metabolism and disease state
• Technologies to assess gene function in tissue-specific manner for MOA and target tissue specificity
• In vivo models with improved assessment of human specific ADME and safety / toxicity
• In vitro platforms that robustly reproduce clinical indications, ADME, and clinical safety / toxicity
• Label free assay / non-invasive in vivo technologies capable of translating from basic to clinical for MOA, drug distribution, and safety / toxicity

Areas of Interest:

• Quick-turnaround mid-density expression, genotyping, protein expression platforms
• Technologies that can perform multiplexed biomarker analysis with wide dynamic range
  • RNA, proteins, peptides, and / or small molecules
  • Animals and / or clinic
  • More streamlined with fewer repeats due to dilutions for individual analytes qualified biomarkers
• Identify vendors / academics that have identified and / or discover / validate / qualify biomarkers
  • Translation to humans (cell lines → human cells → animals → humans)
  • Target engagement, pharmacologic activity, efficacy, and toxicity
  • Sources of samples or model systems for biomarker discovery and development

Areas of Interest:

• Improved miniaturized high throughput assays for MoA and toxicity assays
  • Toxicity Assessment with limited amounts of compounds
  • Continuous kinetic cell-based assays of second messenger kinetics (Ca++, cAMP, phosphorylation, Ion Channels, etc) for determination of On rate, Off rate, desensitization in cellular contest
  • Measurements of the GPCR-mediated physiological responses, including heterodimer formation
  • Cellular protein-protein interactions
  • Technologies for automated siRNA and cDNA screening
• Physiological cellular models and translational ex vivo cellular models
  • In vitro / ex vivo / in vivo predictive models
  • Improved technologies for primary cell immortalization of disease tissues
  • Metabolically competent hepatocyte-like cellular systems
  • Improvement on BACMAM vectors for cell transfection
  • Disease predictive physiological cellular models
• High throughput imaging and flow cytometry platforms
  • Advanced cellular image analysis software
  • Imaging-based tools to measure morphological / biomechanical changes in cells
  • High throughput flow-based imaging for screening primary stem cells
  • 3D-imaging tools and analysis software
  • Novel fluorophores for measurements of the cellular changes, including structural proteins

Areas of Interest (Chemical Synthesis):

• Improved reactions
  • Asymmetric cyclopropanation
  • Selective functionalization of heterocyclic compounds
  • Nitroreductases as a platform for accessing chiral aliphatic amines, and anilines
  • Greener oxidations
• Method to determine the cost of separations for scale-up reactions
• Enzyme immobilization
• t-Bu cross-coupling
• Automation tools for DOE experiments
• Analysis and purification of lipids
• 14C labeled carbonylation
• N=O chemistry
• Preparation of alkyl fluorides
• C-H oxidations
• Reactions to introduce fluorine and CF3

Areas of Interest (Purification):

• Scalable membrane separations
• "One shot" separations system

Areas of Interest:

• ADME models and databases
  • Large, diverse datasets for less common metabolic pathways, such as aldehyde oxidase, sulfotransferases, BCRP, and other transporters, etc
  • Models for observable phenomena that are composites of multiple processes, eg, bioavailability, volume of distribution, clearance
• Ligand design
  • Fragment-based de novo design software
  • Assessment of relative synthetic tractability with performance appropriate for prioritizing thousands to millions of novel structures
• Protein and protein-ligand modeling
  • Reliable screening of multiple mutations including multiple templates
  • Antibody structure prediction and protein loop prediction
  • Flexible backbone design and simultaneous de novo modeling of multiple loops
  • Ab-initio prediction of protein structures, including cases where predicted domain is part of a multi-domain protein or complex
  • 3D docking software for pose prediction that incorporates binding site flexibility and alternate protonation states
• Molecular mechanics and dynamics
  • Setup and analysis software for MD calculations
  • Molecular mechanics force-fields that can reliably model geometries and energies of small molecules and proteins including solvent effects
• Virtual screening for lead finding and lead optimization
  • Ligand or protein-based methods to find actives more efficiently with demonstrated performance on experimental datasets for multiple targets
  • Ligand or protein-based methods to find actives representing greater diversity of chemical classes with demonstrated performance on experimental datasets for multiple targets
  • Improved scoring for compound ranking that include explicit waters or configurational entropy with demonstrated ranking performance on experimental datasets for multiple targets in 3D docking experiments (eg, methods)

Areas of Interest:

• Microfluidics
  • Coupling microfluidics to conventional automation and analytical tools to maximize productivity, eg, Empyrean microfluidic UV / Vis plate reader
  • Miniaturization of screening tools compatible with organic solvents capabilities for analytical measurements, reactions, formulations
• Nanoscale sample transfer automation
  • 1 –100 nL range with improved precision / accuracy and speed, solvent compatibility
  • Acoustic, inkjet, piezo-based technologies
• MicroArray type methodologies applied to chemical / analytical questions
• Consolidation of sample prep unit operations with analytical autosamplers
  • Sample filtration, dilution, quenching, pretreatment, etc, for compounds, tablets, etc
• Coupling conventional HTS liquid handling approaches with techniques beyond plate readers
• Automation of routine sample / buffer preparation
• Quick-turnaround mid-density expression, genotyping, protein expression platforms

Areas of Interest:

• Knowledge management and data-mining tools
  • Finding and accessing existing data
  • Ability to integrate external and internal data sets
  • Technology to improve information connectivity and sharing within MRL as well as with external partners
  • Information and document tagging technologies for smart retrieval of information and documents for export and data / text-mining
  • Technology to support the reusability of information, eg, through collaborative / structured authoring
  • Knowledge capture technology to capture tacit knowledge as well as when knowledge is generated through collaborative research
• Collaboration tools
  • Collaborative contribution / decision-making tools, eg, such as predictive market technology
• Workflow management
  • Ability to track work requests between groups and perform resource management / prioritization
• In vivo information technology platforms
  • Global in vivo database and analytical platform for preclinical data and ability to compare associated clinical data
  • Animal facility management tools
• Modeling, and predictive analysis capabilities that:
  • Allow better prediction of in vivo (human) drug performance based on in vitro testing
  • Sharing of macromolecular structure models
• Efficient, easy-to-use software for visualizing, manipulating, and processing large amount of data
  • Multidimensional data analysis and reporting tools

Areas of Interest:

• Improved efficiency of analytical workflows
  • Fast and high throughput analysis tools
  • More efficient analytical method development
  • Novel PAT tools
  • Automation of analysis
• Methods to analyze large molecules (siRNAs, peptides, polymers), biologics, and vaccines
• Improved platform analytical tools (HPLC, MS, etc) that require smaller samples, including microfluidic devices to run complex analytical assays