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

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 injury residence delivery model Robert Langer PI – biotechnology, materials, drug delivery Aim 1. Microbe formulations Giovanni Traverso compatible with gastric residence. Collaborator - gastroenterologist, devices, drug delivery Alison Hayward Aim 2. Device safety for spaceflight Veterinarian - animal models, drug delivery and in vivo validation. Miguel Jimenez Postdoc – synthetic and chemical biology, microbiology 2

Koch Institute of Integrative Cancer Research 3

The Langer Lab @ MIT 4

gastrointestinal delivery “GI group” @ Langer Lab 5

Physical Modes of Delivery Microneedle systems Adherence Solutions Figure 4. Therapeutic use concept of the microneedle pill. Both hollow and solid microneedles could be used. In both cases, the pill’s needles Ultrasound-based systems High-throughput formulation dev Dosage form Texturing Inflammation targeting Novel Formulations

Undergraduate macrocyclic [Si] [Si] RCM 2007 - 2011 ring-closing metathesis Stuart Schreiber of vinylsilanes E selective R 1 R 1 Damian Young Harvard University Ph.D. yeast sensor for 2011 - 2017 low-cost point-of-care Virginia Cornish pathogen detection Columbia University Postdoctoral microbiome 2017 – current drug delivery Robert Langer in the GI tract MIT 7

The Cornish Group 8

Undergraduate macrocyclic [Si] [Si] RCM 2007 - 2011 ring-closing metathesis Stuart Schreiber of vinylsilanes E selective R 1 R 1 Damian Young Harvard University Ph.D. yeast sensor for 2011 - 2017 low-cost point-of-care Virginia Cornish pathogen detection Columbia University Postdoctoral microbiome 2017 – current drug delivery Robert Langer in the GI tract MIT 9

Synthetic biology means building with DNA natural cell synthetic cell 10

synthetic biological systems are used for basic research and practical applications basic research applications 11

powerful applications of synthesis have been practical dyes drugs plastics therapeutic yeast-made chimeric antigen receptor antibodies drugs (CAR-T cells) 12

team & project overview gastric microbial stomach injury residence delivery model Robert Langer PI – biotechnology, materials, drug delivery Aim 1. Microbe formulations Giovanni Traverso compatible with gastric residence. Collaborator - gastroenterologist, devices, drug delivery Alison Hayward Aim 2. Device safety for spaceflight Veterinarian - animal models, drug delivery and in vivo validation. Miguel Jimenez Postdoc – synthetic and chemical biology, microbiology 13

microbes in the GI tract affect human health and development microbiome human microbe 3x10 13 4x10 13 cells genes 2x10 4 10 5 -10 6 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). 14 Q in, J. et al. A hum an gut m icrobial gene catalogue established by m etagenom ic sequencing. Nature 464, 59–65 (2010).

how can we modulate the microbiome? probiotics prebiotics Antibiotics Diet Mimee, M., Citorik, R. J. & Lu, T. K. Microbiome therapeutics — Advances and challenges. Advanced Drug Delivery Reviews 105, Part A, 44–54 (2016). 15

engineered microbes enable selective modulation selective modulation probiotics prebiotics Antibiotics Diet Mimee, M., Citorik, R. J. & Lu, T. K. Microbiome therapeutics — Advances and challenges. Advanced Drug Delivery Reviews 105, Part A, 44–54 (2016). 16

delivery remains a major challenge to translation formulation and delivery probiotics remain major challenges for translation daily enteric pills - low viability (freeze drying) - short lived effect (rapid clearance) prebiotics Antibiotics Diet Mimee, M., Citorik, R. J. & Lu, T. K. Microbiome therapeutics — Advances and challenges. Advanced Drug Delivery Reviews 105, Part A, 44–54 (2016). 17

AIM 1: develop formulations of live microbes compatible with gastric residence microbe + formulation + dosage form 18

GI-resident devices for long-term microbiome modulation gastric residence elastomeric core rigid arm microbial formulation 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., 19 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).

gastric resident platform for delivery 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. & 20 Traverso, G. Science Translational Medicine 8, 365ra157-365ra157 (2016).

validated in vivo large animal model 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). 21

current platform persists multiple weeks 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. & 22 Traverso, G. Science Translational Medicine 8, 365ra157-365ra157 (2016).

hollow arms can be loaded with formulation of choice 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., 23 Nowak, M. A., Langer, R. & Traverso, G. Nature Communications 9, 2 (2018)

AIM 1: develop formulations of live microbes compatible with gastric residence microbe + formulation + dosage form 24

high throughput formulation screening pipeline microbe culture alive ? or + dead ? high throughput screening compound library 25

AIM 2: device safety for spaceflight and in vivo validation. stomach injury model microbe formulation viability in simulated microgravity during launch during microgravity 26 Lynch, S. V., M ukundakrishnan, K., Benoit, M . R., Ayyaswam y, P. S. & M atin, A. Appl. Environ. M icrobiol. 72, 7701–7710 (2006).

what are good analogues for defining potential risk from gastric resident systems? stomach injury model What force levels? Other tests? Equipment availability? 27

what are good analogues for defining microbial formulation efficacy? Collaborators with previous experience? How to validate? Equipment availability? Compatibility with gastric-resident system? 28

science challenges : what is the roadmap to implementation in astronauts? translational medicine pipeline earth-based space-based design in vitro (chemical) in vitro (cells) ground analogue in vivo (animal) ??? in vivo parabolic flight (human healthy) in vivo space station (human patient) 29

career challenges : what is the roadmap to research at intersection of basic + applied research? Synthetic chemistry Genetic engineering Human health Space health 30

Thank you! Device development Assay development Cell culture - Tiffany Hua - Johanna L’Heureux - Zach Villaverde - Simo Pajovic - Kait Hess - Afeefah Khazi-Syed PI & collaborator Animal experiments Space flight advice - Robert Langer - Alison Hayward Dava Newman - - Gio Traverso - Joy Collins 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 31