Embed Size (px)
Citation preview
Erich Izdepski, CTO of BTS
Teaming Overview and Objectives
Project Overview
• BTS wants to join a team that believes team collaboration will improve the project outcome
• Our team offers our BIFROST cloud platform, developed with DARPA funds, as an asset for data sharing and cloud analytics.
• No cost for BIFROST other than web hosting and software engineering operations and maintenance
• Our platform and capabilities can help on any TA• Currently providing cloud-based data search,
sharing and analysis platform to DARPA/BARDA
• Our cloud-based system, BIFROST, helps organizations share data and analytics making your team more efficient
• BIFROST features:• Share experiments, datasets, and reports/papers/forms• Index all content and provides advanced search• Securely share data between teams, with auditing• Run automated processes, like QA/QC• Provide cloud servers for heavy computing loads• Data visualization• Backed by expert cloud engineers and architects
Impact• Track project data and documents from all teams
in a single, secure repository with search• Easy for PM/PI to review progress• Simpler sharing/communication with DARPA on
all projects aspects since in BIFROST• Improve collaboration for a geographically
dispersed team• Leverage cloud storage and compute
Come see the poster session demo!
Erich Izdepski, CTO of BTS – [email protected] – 703.906.57521
Distribution Statement 2
John Nelson, GE Research
Teaming Overview and Objectives
Project Overview
• GE Research is one of the most diverse industrial research facility in the world
• Current team has expertise in molecular biology, cell biology, systems integration, automation (platforms for single use processing), complex fluid architecture
Partner needs:• DNA creation automation• RNA therapy formulations• Human subject testing• GMP manufacturing
• We have previously developed Rolling Circle Amplification (RCA) to rapidly produce gram quantities of DNA that can be utilized as is, or converted to RNA for therapy needs. We have experience in industrializing manual workflows and fabricating functionally closed automated systems to perform multi-step scaleup of biologics along with in-line QC, compatible with GMP requirements. This paired with rapid milligram- to gram-scale biosynthetic production of DNA and RNA constructs from initial templates enables the capability to rapidly produce nucleic acid-based therapeutics on-demand at the point of need.
Impact• Our goal is to assemble a team capable of implementing a
realistic plan for accomplishing the DARPA goals towards rapid generation of nucleic acid therapies.
• These therapies revolve around DNA vaccines, DNA expression constructs, mRNA vaccines and mRNA expression constructs.
• Unique metrics:• Nucleic acid product <7 day workflow• Design for GMP• FDA-approved safety profile
Contact Information – [email protected]– (518) 387-7272
Synthesize DNA
construct
Amplify DNA by RCA,
purification
Optional-RNA
FormulationPurify/Aliquot
Partner need Partner need
Human Testing
Partner need
Closed system engineering/Disposables
Jeffrey Way/Pamela Silver, Harvard Medical School, Systems Biology
Teaming Overview and Objectives
Project Overview
• Existing team members and partners: Pamela Silver, Jeffrey Way – numerous post-docs and grad students
• Relevant experience (major accomplishments, publications, etc.)- Extensive synthetic biology and protein engineering experience, mouse testing, commercialization
• Institutional assets - Design capabilities, wet labs, animal facilities, everything
• For which technical challenges are you seeking collaborators? –Building a box that makes (amplifies) nucleic acid on site
• Describe clearly what the team is trying to achieve – We want to build a non-viral, non-immunogenic protein-based nucleic acid delivery system that allows administration of nucleic acid assembled on-site into a patient. The nucleic acid encodes therapeutic protein(s)
• Succinctly describe and/or illustrate your vision to accomplish the technical areas – (1) Amplify NA encoding therapeutic proteins, derived from a panel corresponding to all approved proteins, on site, using a compact device; (2) Administer (inject/inhale); (3) DNA enters cells by a virus-like mechanism, is expressed, does not replicate, goes away if necessary
• Describe your approach to technical challenges that must be overcome – (1) optimizing NA uptake into cells; (2) building a physical device for amplification (not our strong point); (3) dried-down formulation of delivery proteins that carry DNA into cells
Impact• What is the anticipated impact of the team’s success?
• Technique: non-viral protein-based delivery = game changer for delivering nucleic acids
• Capability: Treat warfighters behind enemy lines• List of potential applications.
• Safe and easy on-site gene therapy• What unique metrics and milestones will the team aim to
achieve?• Non-viral, non-detergent, non-immunogenic protein-
based delivery of nucleic acids in vitro, then in vivo• Injection system with a screen interface – push a button
to choose drug, wait 30 minutes, then inject• How will the team pursue transition of this technology?
• Startup biotech company
Contact Information – [email protected]– 617-372-2019 4
+
Ichor Medical Systems: In Vivo Nucleic Acid Delivery
Teaming Overview and Objectives
Project Overview
Participant in DARPA ADEPT-PROTECT & P3 programs
>70 publications using TDS electroporation Seeking collaborators requiring expertise in
in vivo nucleic acid delivery / nucleic acid regulatory expertise
TDS® electroporation-based delivery platform for in vivo delivery of DNA or RNA Experts in clinical translation of electroporation-mediated nucleic acid delivery TDS used for nucleic acid delivery in >30 clinical trials in US, Europe, UK, Africa, and Asia TDS nucleic acid delivery performed in 15 animal species Developed animal models for evaluation of nucleic acid-based protein expression Expertise in CMC requirements for nucleic acid delivery to humans
Impact Provide in vivo delivery of DNA/RNA
constructs to evaluate formulation, efficacy, & safety
Establish cGMP DNA/RNA release criteria Evaluate storage and working stability Develop potency assays to support rapid
clinical use Create CMC template for regulatory
submissionswww.ichorms.com ‖ Claire Evans: [email protected] ‖ (858) 550-2022 x110
Infectious Disease Research Institute Team IDRI
Teaming Overview and Objectives
Project Overview
• IDRI: co-PIs Amit Khandhar, PhD (materials scientist) and Jesse Erasmus, PhD (RNA molecular virologist)
• Aldevron: RNA manufacturing and enzyme supply partner• Gennova: Southeast Asia manufacturing partner• Major accomplishments:
• Erasmus, Khandhar et al, Molecular Therapy, 2018• US Patent Application PCT/US2018/037783• RNA manufacturing scale: 200 mg; cGMP compatible
process• NLC manufacturing scale: 1,000 ml
• Institutional assets: cGMP facility capable of manufacturing NLC up to 200 L scale
• We are seeking to team with engineers in the automotive and energy sector to transfer our established technology to a fully mobile system for DARPA NOW
Impact• Our two-vialed approach provides an agile and target-
independent mechanism to rapidly deliver RNA-encoded countermeasures
• Stable and stockpiled formulation eliminates need for on-site formulation manufacturing, freeing capacity for streamlined RNA manufacturing
• Potential applications enabled by this technology • Mobile end-to-end cGMP manufactured RNA
countermeasure• Novel RNA synthesis processes• Tailor-made formulations for various delivery routes
• Unique metrics and milestones• Streamlined RNA synthesis process for
transferability to a mobile platform
Amit Khandhar – [email protected] – 206-858-6055 6
NLCstock-pile
stable for >1 year at 25°C
“Plug-and-play” = target adaptable
• Two-vial approach enables instant RNA formulation (no encapsulation)
• Formulation and RNA synthesis raw materials readily available
• saRNA provides dose sparing
From sequence ID
to RNA in2-3 weeks
Self-amplifying RNA (saRNA)
Nanostructured Lipid Carrier (NLC)
Formulate by bedside
mixing
Self-contained mobile GMP facility
Erasmus/Khandhar
Immediate DNA Counteragent SystemPI: Dr. Stephen Hughes Institution: Applied DNA Sciences LineaRx Team
Teaming Overview and Objectives• Confirmed Team: LineaRx (subsidiary of Applied DNA Sciences); Hudson Robotics
• Relevant experience: LineaRx commercial large gram-scale PCR production and gene therapy design and key personnel holding relevant Ph.Ds, DARPA/DoD award PI experience, commercial transitions, enterprise IT implementations; Hudson Robotics offers commercial data collection software, robotics, and integration of advanced instrument clusters.
• Institutional assets: LineaRx proprietary continuous PCR-based DNA production; Hudson advanced AI software / database applications for remote robotic integration of laboratory equipment platforms and on-demand sample collection and sequencing.
• Collaborators sought for technical challenges: Analytical systems with remote continuous datalinks to DNA therapeutic production; photolithographic production of oligonucleotides; M1135 vehicle communications knowledge; and design of M53 JSGPM drug hydrodynamic delivery systems.
Impact• Technique and Capability: Roadmap to deliver ultrapersonal DNA therapeutics at
point of diagnosis. Primary focus on nucleic acid therapeutic countermeasures in hundreds of doses to soldiers in the field, ultimately within 24 hours.
• Metrics and milestones: 1) Demonstrate miniaturized continuous GMP production unit for synthesis of oligonucleotides and utilization of these oligos in continuous PCR to produce durable long-lasting targeted terminally-mediated DNA therapeutic for hydrodynamic delivery into soldiers. 2) Demonstrate analytical detection equipment in miniaturized mobile unit for use on the M1135 vehicle with remote electronic transmission of sample analyses straight from and back to the soldier;
• Transition partnering discussions are in progress with such organizations as US Army lab in Natick, Aberdeen proving grounds (partnered in previous DoD CRADA), CDC and CBRN for defense and commercialized medicines.
Project Overview• The proposed system will be an integrated platform to detect, capture and identify biological threats on the battlefield with a mobile analytical
component of the M1135 armed forces detection and surveillance vehicle; data communications to remote facility such as CBRN/CDC using AI-enabled algorithms to identify biothreats and countermeasure sequences which are transmitted to the point of care for local oligo synthesis, DNA production, purification, formulation, testing, finish and fill into vials and eventually to soldiers.
• A rapid instrumentation cluster already developed will be obtained (modeled after DHS TSA airport systems), including miniaturized gas chromatography, liquid chromatography and Raman spectroscopy to detect microbes. Once detected we propose to add new technology to capture and sequence DNA from these microbes. That sequence information, obtained in the field, will then be transmitted in real time to the CDC or other facility where known libraries of biothreats and countermeasures exist, which can be used to calculate a candidate DNA therapy, which will then be transmitted electronically back to a second local unit for production and delivery, to be demonstrated here on 2 DNA targets.
• Linear DNA-based countermeasures using nucleic acid sequences derived from previous step will have added to them novel aptamer sequence elements at their ends, which upon production, will improve uptake expression in the cell. A mobile miniaturized continuous oligonucleotide synthesis and polymerase chain reaction (PCR) manufacture with GMP processes will target 12 - 24 hour hours completion from sample collection.
• The proposed project will consist of 3 phases: 1) Manufacture doses in < 7 days: an alpha-prototype of a miniaturized on-site detection, capture and screening of biothreats with air-gapped end-to-end system to synthesize, purify, analyze, formulate, fill and finish for 1 known DNA target. Engagement with FDA for GMP and quality process reviews.2) Manufacture doses in 1-2 days: Integrate modules from Phase 1 through fill-finish vialing, expand to second DNA target and demonstrate remote communications to confirm target, and perform GMP production of sequences for DNA countermeasures in animal models; engagement with FDA.3) Manufacture doses in 24 hours: Phase I human clinical study targeting a DoD-relevant disease. Next-gen enhancements in delivery through M53 JSGPM drug delivery system.
Dr. Stephen Hughes – [email protected] – 1-309-863-8096
Founded: 2010 IPO: 2018 Focus: exclusively on mRNA
therapeutics and vaccines Employees: 800+; ~50% with
Ph.D., MD, JD, or Master’s degrees Pipeline: 20+ development
programs across 4 therapeutic areas: infectious disease, immuno-oncology, rare disease, and cardiovascular disease; 4 programs in or preparing for Ph. 2
Clinical data: 10 positive Ph. 1 readouts (including 6 intramuscular vaccines and 1 IV administered mRNA-encoded antibody)
CMC: 70 GMP batches manufactured in last 14 months
Publications: ~30 peer-reviewed publications in the last few years
Select partners:
Eliot Green – [email protected] 8
Moderna headquarters, Cambridge, MAModerna’s 200,000 sq. ft. manufacturing facility, Norwood, MA
Next step: additional optimization to enable even faster cycle times and miniaturization to increase capacity and portability
Tissue SamplesTumor (biopsy) and
Normal (blood)
Next Generation Sequencing (NGS)
Mutations identified in protein neoantigen and major histocompatibility
complex Vaccine DesignUp to 34 neoantigensAutomated algorithm
integrated with workflow
Administration
ManufacturingManufacturing of mRNA
Aim for one lot per patient
70 unique PCV batches manufactured to date; ~130 additional batches planned through YE 2020
3’x4
’ foo
tprin
t
Manufacturing of our Personalized Cancer Vaccine (PCV)
Current 50-60 day turnaround time
© 2018 Precision NanoSystems Inc 9
The Leading Platform for Mobile Medical Countermeasure Manufacturing of Nanoparticle Enabled Nucleic Acid Therapeutics. Final Drug Product
Available in Record TimeNanoAssemblrTM
Continuous Flow Platform
mRNA, Replicon, DNA, siRNA
GenVoyTM Lipid NanoparticlesOr other deliver components
GMP CompliantAutomated for fast and reproducible results
Minimal operator expertise requiredFast setup and small footprint enable flexible deployment
Configurable platform : mL to 100s L
Any nucleic acid payloadFinal Doses
Full manufacturing completed within
hours
Precision NanoSystems
Core Technologies
GenVoyTM Lipid Nanoparticles
NxGenTM Microfluidics for nanoparticle manufacturing
Impact
• A fully automated drug product manufacturing system with minimal facility requirements
• Rapid response and in country manufacturing• Reproducible drug product manufacturing with
minimal operator expertise• Platform for rapid response, mobile manufacturing,
single to thousands of doses• Interoperable with PNI’s commercial development
systems, for rapid deployment of novel therapeutics.
• 4 commercial instruments, reagents and technical expertise for a complete solution
• >350 installs; 100 pharma/biotech, including over 60 gene therapy companies
• > 150 publications using NanoAssemblr platform in Cell, PNAS, ADDR, ACS Nano…
• Network of collaborators with expertise from RNA manufacturing to drug product fill & finish
• Preferred vendor for several BARDA and DARPA performers
Industry Leadership Project Outcome
Modular Drug Design Enables Rapid Response by Varying Payload
Contact: [email protected]
The Leading Platform for Mobile Medical Countermeasure Manufacturing of Nanoparticle Enabled Nucleic Acid Therapeutics.
Contact: [email protected]
BBN | PI: M. Rogers | NOW
Teaming Overview Impact
Dr. Aaron Adler ([email protected], 410-290-2034), Ms. Helen Scott ([email protected], 617-873-7405) 10
BBN is a world technology leader for solving significant and complex problems in a wide range of areas
Microfluidics User InterfaceMachine Learning GuidedEnzyme Engineering
Automation &Miniaturization
• Expertise in designing systems for enzymatic DNA synthesis
• Constraints-based ab initio modeling • Computationally-guided protein engineering• Nucleic acid computational and bioinformatics analysis• Protocols and software for absolute quantitation
Seeking Partners with:• Expertise in Good Manufacturing Practices of DNA• Expertise in scalable sequencing
• Transition partner & manufacturing ability• Materials qualification and verification for DoD deployment• Experience in operating in military scenarios
• High fidelity de novo nucleic acid synthesis• Reduced timelines for manufacturing of nucleic acid and
protein based therapeutics• Create an integrated system deployable in austere
environments
https://synbiotools.com/
Elsie – Scripps Research – Baran Lab – Dr. Julien VantouroutA Redox Neutral Platform for Oligonucleotide Synthesis
Teaming Overview and Objectives
Project Overview
• Prof. Phil Baran (PI), Dr. Julien Vantourout (Staff Scientist),Dr. Natalia Muñoz Padial (Postdoc), Kyle Knouse (PhDstudent)
• P(V) platform already validated (4 reagents – 3 linkages)• Science paper published in 2018• Nature paper in preparation• Oligopeptide synthesizer and HPLC purification system
available in our laboratory• We are seeking collaborators to implement our P(V)
platform to mobile devices.• We are also seeking collaborators to help with formulation
and rapid analysis of the prepared oligonucleotides
Impact• Simple protocol and stable reagents• P(V) platform is as fast as P(III)• P(V) platform is not sensitive to air or moisture• This technology will allow access to chimeric sequences
Julien Vantourout– [email protected] – (858) 209 3244 11
• Ideality in phophorothioate oligonucleotide construction• Minimization of concession steps• Easy and fast implementation• Direct modification of native sequences• Complete control of chemoselectivity and stereoselectivity• Enabling access to new and unprecedented chemical space
Stereorandom Stereoselective
Arum Han, Texas A&M University, CREATE
Teaming Overview and Objectives
Project Overview
• Arum Han, Texas A&M University: High-throughput microfluidics lab-on-a-chip development
• Paul de Figueiredo, Texas A&M University: Microbiology, including category B Select Agents (for nucleic acid target selection)
• Adam Abate, UCSF: Droplet microfluidics and DNA synthesis
• Expertise in Computational Biology• Expertise in GMP Manufacturing
• Cole et al. (2017). Printed droplet microfluidics for on demand dispensing of picoliter droplets and cells. PNAS.
• Kim et al. (2015). A High-throughput Microfluidic Single-Cell Screening Platform Capable of Selective Cell Extraction. Lab on a Chip.
• The CREATE platform: Combinatorial Recombinant Enzyme-directed de novo nucleic Acid synthesis Technology
• A massively parallel droplet microfluidic platform for the on-demand, de novo assembly of nucleic acids
• Microfluidics allows for miniaturization and efficient reagent handling/utilization
• Microdroplets as bioreactors, deterministically selecting, printing, and combining these droplets
• Nucleic acid synthesis can be achieved through combinatorial assembly of smaller pre-synthesized oligomers, using an iterative process
Impact• Parallelized, enzymatic and automated on-demand nucleic
acid synthesis (DNA or RNA) without the need for conventional oligonucleotide synthesis.
• Efficient reagent usage on a portable field-deployable manufacturing platform
• Platform can be extended to direct de novo protein synthesis
• Applications: Vaccines, therapeutics, and diagnostic reagents
• IP protection, technology transfer through licensing and startup company creation
Arum Han – [email protected] – 979-458-8854 12
Pre-made cartridges store libraries of k-mer building blocks for synthesis, which are fed to the microfluidic chip
Reagent Pre-Generation
Nucleic Acid Synthesis
Nucleic Acid Isolation/QC
Sarah Milsom, Touchlight Genetics Ltd
Teaming Overview and Objectives• Existing team: Touchlight Genetics DNA process dev team,
delivery partners (device, single step lipid – TBD)• Experience: Process development (GMP), machine prototype
building, vaccine development• Assets: Patented and scaled DNA process, backbone free DNA
vector, GMP facilities, existing machine, research facility and delivery technology options (EP device and lipid - collaborations)
• Seeking collaborators for:• Starting template fragment/GOI synthesis• DNA drug delivery technologies• Machine development / automation partner
Impact• Impact: With the level of existing development (DNA + delivery)
and a rapid fragment synthesis partner, the project could develop an end to end solution
• Potential applications: on demand vaccines), personalized vaccines, DNA launched antibodies, gene therapy, etc.
• Unique metrics and milestones:• Fully closed loop drug-grade DNA manufacturing and
purification machine• 1-day amplification of 1-2g batch
• Approach to transition: Further collaboration with defense, commercialization for personalized cancer vaccines
Contact Information – [email protected] 13
Project aim: Develop 24-hour DNA synthesis-to-delivery system leveraging Touchlight’s enzymatic DNA machine
Status: Multi kb blocks, 1/3000 error rate, multi species generated
from enzymatic assembly
Project objective:Improve length and fidelity of
fragment synthesis / assembly; Develop synthetic clonal selection
Touchlight’s technologySynthesise /
assemble clonal template
Automated enzymatic amplification from
single template vector
Automated, in-line DSP (enzymatic +
single step column)Formulate for
delivery
Status: Benchtop process est. (isothermal, multigram, GMP, pDNA fidelity); machine prototype functional
(100mg scale)
Project objective:Scale up (e.g. 1-2L=~1-2g);
speed up (1 day process scoped); GMP align and characterise
Status:Single step, closed loop DSP
established for GMP multi-gram scale batches
Project objective:Build in column and aseptic filter step, adapt enzymatic
purification for starting material
Status: Multiple formulations and
devices approved for clinical use
Project objective:Identify best option based on
target product profile; improve dose sparing
Seeking collaboratorSeeking collaborator
Seeking collaborator – automation / machine
