Gastrointestinal Devices for Long-T erm In Situ Delivery of - - PowerPoint PPT Presentation

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Gastrointestinal Devices for Long-T erm In Situ Delivery of - - PowerPoint PPT Presentation

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Gastrointestinal Devices for Long-T erm In Situ Delivery of Therapeutic Microbes Miguel Jimenez Postdoctoral Associate Langer Lab Koch Institute MIT TRISH Virtual Forum, May 23, 2018 team & project overview gastric microbial stomach

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Gastrointestinal Devices for Long-T erm In Situ Delivery of Therapeutic Microbes

Miguel Jimenez

Postdoctoral Associate Langer Lab Koch Institute MIT

TRISH Virtual Forum, May 23, 2018

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team & project overview

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Aim 1. Microbe formulations compatible with gastric residence. Aim 2. Device safety for spaceflight and in vivo validation. gastric residence stomach injury model Robert Langer

PI – biotechnology, materials, drug delivery

Giovanni Traverso

Collaborator - gastroenterologist, devices, drug delivery

Alison Hayward

Veterinarian - animal models, drug delivery

Miguel Jimenez

Postdoc – synthetic and chemical biology, microbiology

microbial delivery

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Koch Institute of Integrative Cancer Research

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The Langer Lab @ MIT

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gastrointestinal delivery “GI group” @ Langer Lab

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Figure 4. Therapeutic use concept of the microneedle pill. Both hollow and solid microneedles could be used. In both cases, the pill’s needles

Physical Modes of Delivery Adherence Solutions Microneedle systems Novel Formulations Ultrasound-based systems High-throughput formulation dev Inflammation targeting Dosage form Texturing

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macrocyclic ring-closing metathesis

  • f vinylsilanes

microbiome drug delivery in the GI tract Undergraduate 2007 - 2011 Stuart Schreiber Damian Young Harvard University Postdoctoral 2017 – current Robert Langer MIT yeast sensor for low-cost point-of-care pathogen detection Ph.D. 2011 - 2017 Virginia Cornish Columbia University

R1 R1 [Si] E selective RCM [Si]

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The Cornish Group

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macrocyclic ring-closing metathesis

  • f vinylsilanes

microbiome drug delivery in the GI tract Undergraduate 2007 - 2011 Stuart Schreiber Damian Young Harvard University Postdoctoral 2017 – current Robert Langer MIT yeast sensor for low-cost point-of-care pathogen detection Ph.D. 2011 - 2017 Virginia Cornish Columbia University

R1 R1 [Si] E selective RCM [Si]

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Synthetic biology means building with DNA

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natural cell synthetic cell

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synthetic biological systems are used for basic research and practical applications

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applications basic research

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powerful applications of synthesis have been practical

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dyes drugs plastics therapeutic antibodies yeast-made drugs chimeric antigen receptor (CAR-T cells)

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team & project overview

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Aim 1. Microbe formulations compatible with gastric residence. Aim 2. Device safety for spaceflight and in vivo validation. gastric residence stomach injury model Robert Langer

PI – biotechnology, materials, drug delivery

Giovanni Traverso

Collaborator - gastroenterologist, devices, drug delivery

Alison Hayward

Veterinarian - animal models, drug delivery

Miguel Jimenez

Postdoc – synthetic and chemical biology, microbiology

microbial delivery

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microbiome

microbes in the GI tract affect human health and development

Fischbach, M . A. & Segre, J. A. Signaling in Host-Associated M icrobial Com m unities. Cell 164, 1288–1300 (2016). M cFall-Ngai, M . et al. Anim als in a bacterial world, a new im perative for the life sciences. PNAS 110, 3229–3236 (2013). Q in, J. et al. A hum an gut m icrobial gene catalogue established by m etagenom ic sequencing. Nature 464, 59–65 (2010).

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human microbe cells 3x1013 4x1013 genes 2x104 105-106

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how can we modulate the microbiome?

Mimee, M., Citorik, R. J. & Lu, T. K. Microbiome therapeutics — Advances and challenges. Advanced Drug Delivery Reviews 105, Part A, 44–54 (2016). 15

Antibiotics Diet prebiotics probiotics

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engineered microbes enable selective modulation

Mimee, M., Citorik, R. J. & Lu, T. K. Microbiome therapeutics — Advances and challenges. Advanced Drug Delivery Reviews 105, Part A, 44–54 (2016). 16

Antibiotics Diet prebiotics probiotics selective modulation

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delivery remains a major challenge to translation

Mimee, M., Citorik, R. J. & Lu, T. K. Microbiome therapeutics — Advances and challenges. Advanced Drug Delivery Reviews 105, Part A, 44–54 (2016). 17

Antibiotics Diet prebiotics probiotics

formulation and delivery remain major challenges for translation

daily enteric pills

  • low viability (freeze drying)
  • short lived effect (rapid clearance)
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AIM 1: develop formulations of live microbes compatible with gastric residence

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microbe + formulation + dosage form

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GI-resident devices for long-term microbiome modulation

Bellinger, A. M., Jafari, M., Grant, T. M., Zhang, S., Slater, H. C., Wenger, E. A., Mo, S., Lee, Y.-A. L., Mazdiyasni, H., Kogan, L., Barman, R., Cleveland, C., Booth, L., Bensel, T., Minahan, D., Hurowitz, H. M., Tai, T., Daily, J., Nikolic, B., Wood, L., Eckhoff, P. A., Langer, R. & Traverso, G.Science Translational Medicine 8, 365ra157-36 Kirtane, A. R., Abouzid, O., Minahan, D., Bensel, T., Hill, A. L., Selinger, C., Bershteyn, A., Craig, M., Mo, S. S., Mazdiyasni, H., Cleveland, C., Rogner, J., Lee, Y.-A. L., Booth, L., Javid, F., Wu, S. J., Grant, T., Bellinger, A. M., Nikolic, B., Hayward, A., Wood, L., Eckhoff, P. A., Nowak, M. A., Langer, R. & Traverso, G. Nature Communications 9, 2 (2018).

19 elastomeric core rigid arm microbial formulation

gastric residence

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gastric resident platform for delivery

20 Bellinger, A. M., Jafari, M., Grant, T. M., Zhang, S., Slater, H. C., Wenger, E. A., Mo, S., Lee, Y.-A. L., Mazdiyasni, H., Kogan, L., Barman, R., Cleveland, C., Booth, L., Bensel, T., Minahan, D., Hurowitz, H. M., Tai, T., Daily, J., Nikolic, B., Wood, L., Eckhoff, P. A., Langer, R. & Traverso, G. Science Translational Medicine 8, 365ra157-365ra157 (2016).

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validated in vivo large animal model

21 Bellinger, A. M. et al. (Langer & Traverso). Science Translational Medicine 8, 365ra157-365ra157 (2016). Kirtane, A. R. et al. (Langer & Traverso). Nature Communications 9, 2 (2018).

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current platform persists multiple weeks

22 Bellinger, A. M., Jafari, M., Grant, T. M., Zhang, S., Slater, H. C., Wenger, E. A., Mo, S., Lee, Y.-A. L., Mazdiyasni, H., Kogan, L., Barman, R., Cleveland, C., Booth, L., Bensel, T., Minahan, D., Hurowitz, H. M., Tai, T., Daily, J., Nikolic, B., Wood, L., Eckhoff, P. A., Langer, R. & Traverso, G. Science Translational Medicine 8, 365ra157-365ra157 (2016).

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hollow arms can be loaded with formulation of choice

23 Kirtane, A. R., Abouzid, O., Minahan, D., Bensel, T., Hill, A. L., Selinger, C., Bershteyn, A., Craig, M., Mo, S. S., Mazdiyasni, H., Cleveland, C., Rogner, J., Lee, Y.-A. L., Booth, L., Javid, F., Wu, S. J., Grant, T., Bellinger, A. M., Nikolic, B., Hayward, A., Wood, L., Eckhoff, P. A., Nowak, M. A., Langer, R. & Traverso, G. Nature Communications 9, 2 (2018)

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AIM 1: develop formulations of live microbes compatible with gastric residence

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microbe + formulation + dosage form

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+ high throughput formulation screening pipeline

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compound library microbe culture

alive ?

  • r

dead ?

high throughput screening

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AIM 2: device safety for spaceflight and in vivo validation.

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Lynch, S. V., M ukundakrishnan, K., Benoit, M . R., Ayyaswam y, P. S. & M atin, A. Appl. Environ. M icrobiol. 72, 7701–7710 (2006).

stomach injury model microbe formulation viability in simulated microgravity

during launch during microgravity

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what are good analogues for defining potential risk from gastric resident systems?

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stomach injury model What force levels? Other tests? Equipment availability?

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what are good analogues for defining microbial formulation efficacy?

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Collaborators with previous experience? How to validate? Equipment availability? Compatibility with gastric-resident system?

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science challenges: what is the roadmap to implementation in astronauts?

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translational medicine pipeline earth-based space-based design in vitro (chemical) in vitro (cells) ground analogue in vivo (animal) ??? in vivo (human healthy) parabolic flight in vivo (human patient) space station

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career challenges: what is the roadmap to research at intersection of basic + applied research?

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Synthetic chemistry Genetic engineering Human health Space health

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Device development

  • Tiffany Hua
  • Simo Pajovic

Thank you!

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Assay development

  • Johanna L’Heureux
  • Kait Hess

Cell culture

  • Zach Villaverde
  • Afeefah Khazi-Syed

PI & collaborator

  • Robert Langer
  • Gio Traverso

Animal experiments

  • Alison Hayward
  • Joy Collins

Space flight advice

  • Dava Newman

Sponsor and guidance

  • Dorit Donoviel
  • Virginia Wotring
  • Laurence Young

This work is supported by the Translational Research Institute for Space Health through Cooperative Agreement NNX16AO69A