Areas of Interest:

• siRNA delivery platforms for systemic or local administration
  • siRNA conjugates, preferably of defined structure
  • Nanoparticles with superior efficacy and safety margins
• Targeted cytosolic delivery of siRNA conjugates
  • Endosomal escape components and membrane translocation mechanisms for improved RNAi activity
  • Targeting ligands (eg, antibodies, peptides, aptamers, small molecules) for efficient delivery and internalization of oligonucleotides in extra- hepatic tissues, preferably against cell surface receptors upregulated in disease conditions
• Approaches to enhance permeation and distribution of siRNA within tissues
• Formulations for slow-release and oral bioavailability of siRNA conjugates
• Assays and models
  • In vitro screens for compounds that enhance endosomal escape or cytosolic delivery of oligonucleotides
  • Assays for detection and quantitation of cytosolic siRNA in vivo
  • High-throughput and multiplex assays for quantitation of RISC-bound siRNA
  • Assays for quantification of plasma protein binding of siRNA and siRNA conjugates, and for characterization of bound protein
  • Novel MS approaches to quantitative and qualitative analysis of siRNA pharmacokinetics and metabolism
  • Transgenic rodent models for measuring RNAi activities in vivo in all tissues with noninvasive readout and dim to bright signal
  • Phenotypic or disease models in nonhuman primates
• RNA manufacturing
  • Post-synthetic methodology
  • Development of siRNA construct synthesis
  • New advancements in phosphoramidite synthesis and production
  • Improved activation, oxidation, and thiolation reagents and procedures for oligonucleotide synthesis
  • Rapid delivery of small-scale oligonucleotide plates (10 nmol duplexes) including modified nucleotides (eg, 2’-fluoro, 2’-methoxy) while maintaining high sample quality
  • Improved high-throughput, small-scale purification methods
  • Efficient high-volume data processing and management for small-scale plate-based synthesis workflows
  • Advancements in large-scale production of modified siRNA, including solution phase chemistry
  • Improved processes for increased quality, efficiency, and reduced COG for small-, mid- and large-scale oligonucleotide synthesis, including reduction of solvent consumption in large-scale synthesis
  • Large-scale reverse phase purification capability
  • Robust LC-MS method for determination of impurity profile of phosphoramidite raw materials and oligonucleotides (siRNAs)
• siRNA optimization
  • Novel chemistries for:
    • Improving resistance to enzymatic and chemical degradation in circulation and during cellular uptake and trafficking
    • Charge neutralization of siRNA while retaining intrinsic RNAi activity
    • Enhancing Ago2 / RISC incorporation and potency
    • Oligonucleotide modifications that confer increased endosomal escape
    • Improving target specificity
    • Orthogonal chemistries for post-synthetic modifications
    • Approaches to RNA interference that overcome duplex siRNA liabilities, including in vivo local administration demonstration of benefit
  • Predictive bioinformatic and molecular models

Not Interested in:

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

Areas of Interest:

• Oral delivery:
  • Controlled-release technologies capable of enabling QD delivery for compounds with poor colonic absorption or poor solubility (<0.1 mg/mL)
  • Novel fixed-dosed combination technologies to enable dosing flexibility and development speed
  • High drug-load ODT technologies providing rapid disintegration, compatible with amorphous formulations
  • Technologies for tamper resistance / anti-counterfeiting
  • Novel preservative-free liquid or solid formulations approaches for children over age 2 to enable dosing flexibility
  • Novel formulations and devices to meet the specific needs of geriatric patients
  • Novel taste-modification technologies (beyond encapsulation, complexation)
  • Novel approaches to enable rapid, safe intraoral absorption
  • Novel oral protein / peptide delivery systems (eg, insulin)
  • Novel solubilizing excipients with accompanying toxicology package for safety assessment studies
• Injection delivery and devices
  • Novel solubilization technologies for poorly soluble compounds, with supporting safety / tolerability data
  • Novel, safe materials for injectable or implantable sustained-release dose forms
  • Easy-to-use self-injection systems with POC prototypes available
  • Improved liquid / dry reconstitution technologies
  • Devices for delivery of large injection volumes and / or high-viscosity (>25 cP) formulations
  • Infusion systems (IV and subcutaneous delivery) that facilitate hospital and home infusion therapies
  • Liquid formulations that enable room temperature storage and transportation of labile molecules
  • Low-cost injection devices suitable for emerging markets with concept prototypes available
  • Drug-releasing implants, vaginal rings, and intrauterine devices and applicable biodegradable as well as nonbiodegradable biomaterials
• Inhalation/nasal delivery:
  • High-payload unit dose dry-powder inhalers for delivery of >10 mg API, with high efficiency
  • Devices for pediatric respiratory delivery
  • Patient interaction features on inhalers
  • Novel nasal device and formulation platform for insoluble drugs
  • Technologies to enhance patient compliance
• Skin delivery:
  • Novel passive and active (eg, micro needles) transdermal and topical technologies for small molecule and peptide delivery that support high doses (eg, >20 mg)
• Intelligent delivery systems capable of modulated delivery (eg, signal or drug concentration); personalized / feedback control
• Novel half-life extension or novel pro-drug technologies with clinical data (genetic fusion or chemical conjugation)
• Predictive computational tools and in vitro or preclinical models:
  • Approaches to enable mechanistic understanding of how various drug species quantitatively contribute to insoluble drug absorption
  • Modeling drug release from controlled-release / sustained-release dose forms
  • Predictive models for taste assessment
  • Predictive tools for drug precipitation, PPI, and food effects

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

Areas of Interest:

• Predictive disease models beyond mice: rats, rabbits, pigs, dogs and NHP
  • Animal models for cross franchise opportunities
    • Multi-aspects of metabolic syndrome disease state that mimic patients with diabetes, HTN, high cholesterol (diet induced with underlying pathways intact)
    • Humanized immune models: oncology, immunology and biologics
  • Improved models for MRL disease areas
  • Models that are responsive and resistant to standard of care agents (eg, CVD, diabetes and oncology)
• Better safety / PPDM models
  • Humanized, more relevant human (drug) metabolism and safety tox models
  • Genetic tools to generate human polymorphism for metabolism (see below as well)
• Better tools for target validation and in vivo screens
  • Genetic tools/platform across species to make knock-in models (humanized or introduce specific mutations) to validate human genetics, support MOA studies, guide safety / PPDM and differentiate compounds across different stages of development (TIDV to post-PCC)
  • Tools to interrogate targets in tissue specific manner (genetic, viral, directed delivery)
  • Ability to measure disease or efficacy parameters in conscious rodents with higher throughput (microchips, imaging)
  • In vivo models and tools that will reduce cycle time and increase throughput
• AAV Production
  • High-titer, high-volume AAV production for non-clinical applications and POC

Areas of Interest:

• Next generation HT homogenous analytical and label-free assays amenable to high-density plate formats
  • 1536-well plate format filter binding assay
  • Technologies with improved kinetic binding profiling
    • Current kinetic profiling by BIAcore, ProteOn, BIND, and EPIC does not have good throughput (BIAcore, ProteOn) or kinetic rigor (BIND and EPIC)
  • High-throughput microcalorimetry
    • Current art of enthalpy profiling by isothermal titration calorimetry does not have adequate throughput and miniaturization
  • High-throughput immunoprecipitation and (phospho) protein analysis
• Methods to quantify limit of compound solubility in in vitro assays
  • Readers or methods to detect CAC (critical aggregation concentration) with improved sensitivity
• Physiological and translational cellular model
  • Disease predictive physiological cellular models and improved technologies for primary cell immortalization of disease tissues
  • Metabolically competent hepatocyte-like cellular systems
  • Alternative indicative cell models for neurodegeneration (Alzheimer’s, Parkinson’s)
  • 3D and mixed-culture cell models
• High-throughput imaging and flow cytometry platforms
  • Technologies with improved cell imaging and flow cytometry capabilities (eg, acoustic or MS-based)
  • Advanced cellular image analysis software
  • Imaging-based instruments to measure morphological / biomechanical changes in cells
  • Novel fluorophores for measurements of the cellular changes, including structural proteins
• Technologies for identification of specific protein targets for phenotypic screens small molecule actives

Areas of Interest:

• Cutting-edge technology solutions to improve efficiency, process yield, and lower costs for biologics (eg, therapeutic proteins, mAbs, and new modalities) and vaccines
  • Identify / develop automation tools to accelerate early process development including
    • Expression system assessment for biologics and vaccines
    • Scale-down primary recovery and purification
  • Tools to provide lower cost and shorter processes with flexible design
    • Novel expression systems
    • Novel purification tools for lower cost and continuous processing
    • Tools to increase throughput of nonclinical and clinical production and rapid deployment of commercial production such as single-use technology
    • That enable modular facilities for emerging / developing markets
  • Tools to enable process analytical technology
    • Upstream in situ process monitoring of metabolites and products

Areas of Interest:

• High-throughput full-genome technologies for gene expression and genotyping
• Technologies that can perform multiplexed biomarker analysis for
  • Nucleic acids, proteins, peptides, lipids, carbohydrates and / or metabolites
  • Animals and / or human clinical samples
  • High-throughput and wider dynamic range
• Providers that specialize in the discovery / validation / qualification of novel biomarkers
• Providers of biosamples with excellent annotation for biomarker discovery and validation
• Novel and differentiated technologies specialized in enrichment / separation / detection of low-abundance biomarkers, including
  • Advances in mass spectrometry and improvements in chromatography
  • New methods for the isolation of lipoproteins (applicable to both plasma and CSF)
  • Walk-away automation for extracting nucleic acids, homogenizing samples for protein analysis and separating analytes
  • Novel detection methods with improved sensitivity and rapid validation of new analytes
  • Enrichment and detection methodologies for rare cells or microvesicles
• Informatics IT needs / support / tools for high-throughput, mid-density or multiplex platforms
• Sample preparation technologies including those that preserve biological integrity
  • Analyte stabilization systems
  • Blood spotting technologies
  • Improvements in point-of-service assays or specimen transportation to overcome the needs / limitations of current PBMC-based assays (eg, blood volumes / number of cells needed, PBMC preparation costs, loss of viability with freeze / thawing)
• Imaging
  • Emerging cardiac imaging techniques with a focus on heart failure characterization
  • Immune- / inflammation-based imaging agents
  • Pancreatic beta cell imaging agents
• GPR(s) target engagement biomarkers
• Plasma biomarkers to monitor beta cell mass
• Next generation aptamers for proteomic and biomarker discovery and diagnostics
• Emerging and specialized technologies to assist in the evaluation of the functional immune system
  • Clinical assays used to assess immune function / deficiency
  • Inflammation and inflammatory cell biomarkers
  • Immunophenotyping technologies

Areas of Interest:

• C-H functionalization of complex systems
  • Chemoselective fluorination (aryl, alkyl) methodologies
  • C-C bond formation (CF₃, CHF₂, etc)
  • Tandem chemoselective CH activation and CX cross-coupling
  • Direct asymmetric reduction of heterocycles
• Oxidation chemistry:
  • SP³ hybridized carbon oxidation
  • Metabolite synthesis (chemo- or biocatalytic)
• Improved synthetic methodologies:
  • Stereocontrol of quaternary centers
  • t-Bu cross-coupling
  • Asymmetric cyclopropanation
  • Improved methods for incorporation of radio-labels
  • Ether formation under mild conditions
• Green chemical syntheses:
  • Cost-efficient catalytic methods
  • Non-heavy metal mediated oxidation
  • Unconventional reactions under solvent-free conditions
  • Economically viable replacement of transition metals in catalytic reactions
• Chemical methods for improved drug delivery
  • Improved pro-drug methodologies
  • Solid-state characterization and design
• Analytical / prep purification:
  • 2d HPLC screening / purification
  • Prep GC purifications
  • In-line purification and evaporation technologies
  • Scalable membrane separations
• Improved automation capability
  • Solid dispensing
  • Efficient handling of viscous liquids
  • Fully automated reaction platforms
  • Improved DOE tools
• Other chemical technology areas of interest:
  • Enzyme reactions, catalysis, and immobilization
  • Flow chemistry platforms
  • New lead finding technologies
• Structural sciences:
  • Complementary structural methods (SAXS, EM, etc)
  • NMR-guided protein-ligand docking and structure determination, NMR enzymatic assays
  • Nano-crystallization and crystal imaging
  • Automated crystal harvesting, soaking, and freezing
  • Membrane protein crystallography

Areas of Interest:

• ‘Middleware’ software for improved instrument control and data integration, and information sharing between groups
• Software for NMR and MS structure confirmation (small molecule and proteins)
• Next generation data acquisition / method development
• Knowledge management / data mining
• Predictive software tools
• Physical measurements
• Streamlined analytical assays / equipment / workflows

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 knowledge generated through collaborative research
• Collaboration tools
  • Collaborative-contribution / decision-making tools (eg, such as predictive market technology)
• Modeling, and predictive analysis capabilities to improve probability of success (eg, allow better prediction of in vivo [human] drug performance based on in vitro testing)
• Efficient, easy-to-use software for visualizing, manipulating, and processing big data
  • Multidimensional data analysis and reporting tools
• Technologies to improve mobility and ease of use (eg, smart phone / tablet research applications that can be easily accessed by a mobile workforce)
• Technologies to streamline capture and manipulation of lab data from collection from instrumentation through analysis publishing to corporate repositories