{"663760":{"#nid":"663760","#data":{"type":"news","title":"Healing Breath: Researchers Dramatically Improve Inhalable mRNA Therapy","body":[{"value":"\u003Cp\u003EMessenger RNA, or mRNA, has been used to immunize millions of people in just the past few years, leading the world out of a pandemic, and allowing researchers to consider other therapeutic targets for these flexible, effective drugs.\u003C\/p\u003E\r\n\r\n\u003Cp\u003EAmong the most likely targets for future mRNA therapies are the lungs, given the large number of pulmonary diseases, such as the coronavirus, influenza, asthma, cystic fibrosis, and others.\u0026nbsp;\u003C\/p\u003E\r\n\r\n\u003Cp\u003ENow a team of multi-disciplinary investigators from five universities, led by Georgia Tech faculty researchers, has provided a potential path toward that future. In a\u0026nbsp;\u003Ca href=\u0022https:\/\/www.nature.com\/articles\/s41563-022-01404-0\u0022\u003Estudy published Nov. 28 in the journal\u0026nbsp;\u003Cem\u003ENature\u003C\/em\u003E\u0026nbsp;materials\u003C\/a\u003E, they describe polymeric nanoparticle formulations designed specifically for inhalable mRNA delivery, via an easy-to-use nebulizer.\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u0026ldquo;Nanoparticles made of polymers have specific strengths, and the lung happens to be a place where they are very good for delivery,\u0026rdquo; said\u0026nbsp;\u003Ca href=\u0022https:\/\/bme.gatech.edu\/bme\/faculty\/Philip-Santangelo\u0022\u003EPhil Santangelo\u003C\/a\u003E, professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University.\u0026nbsp;\u003C\/p\u003E\r\n\r\n\u003Cp\u003EIn previous work, Santangelo\u0026rsquo;s lab also has developed mRNA payloads transported by lipid nanoparticles. But polymeric nanoparticles which are designed to carry drugs to their destinations have a higher loading capacity and are compatible with many compounds.\u0026nbsp;\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u0026ldquo;In the lung, they\u0026rsquo;re just flat out better,\u0026rdquo; Santangelo added. \u0026ldquo;And we can use them with a wider range of nebulizers. That may not be as important for testing in rodents, but it is when you\u0026rsquo;re talking about getting this into a person.\u0026rdquo;\u003C\/p\u003E\r\n\r\n\u003Ch3\u003E\u003Cstrong\u003EDelivering the Goods\u003C\/strong\u003E\u003C\/h3\u003E\r\n\r\n\u003Cp\u003EPolymers are large molecules comprised of small, repeating molecular building blocks called monomers. For this study, the researchers focused on synthetic, biodegradable polymers called poly(beta-amino-ester)s, or PBAEs. In a\u0026nbsp;\u003Ca href=\u0022https:\/\/petitinstitute.gatech.edu\/news\/easy-deliver-mrna-treatment-shows-promise-stopping-flu-and-covid-19-viruses\u0022\u003Eground-breaking study released last year\u003C\/a\u003E, Santangelo\u0026rsquo;s team demonstrated the strength of PBAE formulations in delivering mRNA that can express the CRISPR Cas13a protein in lung tissue, where it was effective in stopping SARS-CoV-2 (coronavirus).\u003C\/p\u003E\r\n\r\n\u003Cp\u003EIn the latest work, the researchers used a process called combinatorial synthesis \u0026ndash; a method for preparing large numbers of chemical compounds \u0026ndash; to screen 166 different PBAE formulations. One of these, P76, emerged as the best candidate for protein expression, that is, delivering the therapeutic goods efficiently into the lungs of animals, from mice to non-human primates, which makes P76 species agnostic.\u0026nbsp;\u003C\/p\u003E\r\n\r\n\u003Cp\u003ETurns out, the polymer is also compatible with a variety and combination of cargos, which is not typically the case with the delivery of RNAs. But P76 has demonstrated its ability to transport disparate RNAs. So, in addition to being species agnostic, the polymer is mostly cargo agnostic, too.\u003C\/p\u003E\r\n\r\n\u003Cp\u003EUsing P76, the researchers could effectively encapsulate mRNA together with crRNA, which is a guide strand that basically tells the Cas13a protein who it should target. The key to making it all work so well was incorporating organic compounds called thiols into the mix (turning a PBAE into a PBATE), \u0026ldquo;dramatically increasing the utility of the polymer for any CRISPR-based therapeutic candidate,\u0026rdquo; the authors of the study wrote.\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u0026ldquo;With this new polymer, compared to the old one from our previous work, we get much better protein expression,\u0026rdquo; Santangelo said. \u0026ldquo;We can actually decrease dosage by a factor of four, or 400%, and have the same therapeutic effectiveness. That is significant. It\u0026rsquo;s a striking improvement.\u0026rdquo;\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u003Ca href=\u0022https:\/\/sites.gatech.edu\/santangelo\/\u0022\u003ESantangelo\u0026rsquo;s lab\u003C\/a\u003E\u0026nbsp;collaborated with two Georgia Tech faculty members from the\u0026nbsp;\u003Ca href=\u0022https:\/\/www.chemistry.gatech.edu\/\u0022\u003ESchool of Chemistry and Biochemistry\u003C\/a\u003E, Professor\u0026nbsp;\u003Ca href=\u0022http:\/\/www.finnlabresearch.org\/\u0022\u003EM.G. Finn\u003C\/a\u003E\u0026nbsp;and Associate Professor\u0026nbsp;\u003Ca href=\u0022https:\/\/simbac.gatech.edu\/\u0022\u003EJames Gumbart\u003C\/a\u003E, who also is a member of the\u0026nbsp;\u003Ca href=\u0022https:\/\/physics.gatech.edu\/\u0022\u003ESchool of Physics\u003C\/a\u003E. The University of Georgia, University of Louisiana-Lafayette, and Mississippi State University were also part of the study, which involved more than 25 authors.\u0026nbsp;\u003C\/p\u003E\r\n\r\n\u003Cp\u003ETheir work in\u0026nbsp;\u003Cem\u003ENature Materials\u003C\/em\u003E\u0026nbsp;was published on the heels of another nebulizer-based study from the Santangelo team that was\u0026nbsp;\u003Ca href=\u0022https:\/\/onlinelibrary.wiley.com\/doi\/full\/10.1002\/advs.202202771\u0022\u003Epublished in the journal\u0026nbsp;\u003Cem\u003EAdvanced Science\u003C\/em\u003E\u003C\/a\u003E. That work detailed the development of a more efficient, inhalable mRNA medicine to prevent respiratory virus infections like the coronavirus.\u0026nbsp;\u003C\/p\u003E\r\n\r\n\u003Cp\u003EIn both papers, which were supported by the Defense Advanced Research Projects Agency (DARPA), the researchers demonstrated the utility of polymeric formulations for delivering the potent cargo into the lungs.\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u0026ldquo;With these studies we basically wanted to make people aware of new versions of a class of molecules that have lots of advantages over the old ones,\u0026rdquo; Santangelo said. \u0026ldquo;And the reality is, I think, for the nebulization and delivery to the lung, they have big advantages. These polymers make a lot of sense.\u0026rdquo;\u003C\/p\u003E\r\n\r\n\u003Cp\u003EAnd potentially, a lot of cents, too, with the global mRNA therapeutics market expected to exceed $26 billion by 2028.\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u0026nbsp;\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u003Cstrong\u003ECITATION:\u003C\/strong\u003E\u0026nbsp;Laura Rotolo, Daryll Vanover, Nicholas C. Bruno, Hannah E. Peck, Chiara Zurla, Jackelyn Murray, Richard K. Noel, Laura O\u0026rsquo;Farrell, Mariluz Ara\u0026iacute;nga, Nichole Orr-Burks, Jae Yeon Joo, Lorena C. S. Chaves, Younghun Jung, Jared Beyersdorf, Sanjeev Gumber, Ricardo Guerrero-Ferreira, Santiago Cornejo, Merrilee Thoresen,\u0026nbsp;\u003Ca href=\u0022https:\/\/bme.gatech.edu\/bme\/news\/healing-breath-researchers-dramatically-improve-inhalable-mrna-therapy#_msocom_1\u0022 id=\u0022_anchor_1\u0022\u003E[PGR1]\u003C\/a\u003E\u0026nbsp;Alicia K. Olivier, Katie M. Kuo, James C. Gumbart, Amelia R. Woolums, Francois Villinger, Eric R. Lafontaine, Robert J. Hogan, M. G. Finn, and Philip J. Santangelo. \u0026ldquo;Species-agnostic polymeric formulations for inhalable messenger RNA delivery to the lung.\u0026rdquo; (\u003Cem\u003ENature Materials\u003C\/em\u003E, Nov. 28, 2022)\u0026nbsp;doi.org\/10.1038\/s41563-022-01404-0\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u003Cstrong\u003ECOMPETING INTERESTS:\u003C\/strong\u003E\u0026nbsp;Rotolo, Vanover, Bruno, and Santangelo have a provisional patent filing related to this work.\u0026nbsp;Vanover, Zurla, and Santangelo are cofounders of Tether Therapeutics and this study could affect their personal financial statuses. All other authors declare no competing interests.\u003C\/p\u003E\r\n","summary":null,"format":"limited_html"}],"field_subtitle":"","field_summary":[{"value":"\u003Cp\u003EMessenger RNA, or mRNA, has been used to immunize millions of people in just the past few years. Among the most likely targets for future mRNA therapies are the lungs, given the large number of pulmonary diseases, such as the coronavirus, influenza, asthma, cystic fibrosis, and others. Now, a team of multi-disciplinary investigators from five universities, led by Georgia Tech faculty researchers, has provided a potential path toward that future.\u003C\/p\u003E\r\n","format":"limited_html"}],"field_summary_sentence":[{"value":"A team of multi-disciplinary investigators from five universities, led by Georgia Tech faculty researchers, has provided a potential path toward future mRNA therapies."}],"uid":"28153","created_gmt":"2022-12-08 21:46:06","changed_gmt":"2023-03-02 19:42:40","author":"Jerry Grillo","boilerplate_text":"","field_publication":"","field_article_url":"","dateline":{"date":"2022-12-08T00:00:00-05:00","iso_date":"2022-12-08T00:00:00-05:00","tz":"America\/New_York"},"extras":[],"hg_media":{"663758":{"id":"663758","type":"image","title":"Nebulizer","body":null,"created":"1670535672","gmt_created":"2022-12-08 21:41:12","changed":"1670535672","gmt_changed":"2022-12-08 21:41:12","alt":"nebulizer","file":{"fid":"251244","name":"nebulizer.jpg","image_path":"\/sites\/default\/files\/images\/nebulizer.jpg","image_full_path":"http:\/\/www.tlwarc.hg.gatech.edu\/\/sites\/default\/files\/images\/nebulizer.jpg","mime":"image\/jpeg","size":834622,"path_740":"http:\/\/www.tlwarc.hg.gatech.edu\/sites\/default\/files\/styles\/740xx_scale\/public\/images\/nebulizer.jpg?itok=AMvXeLeg"}},"663759":{"id":"663759","type":"image","title":"daryll and phil","body":null,"created":"1670535725","gmt_created":"2022-12-08 21:42:05","changed":"1670535725","gmt_changed":"2022-12-08 21:42:05","alt":"","file":{"fid":"251245","name":"Daryll and Phil.jpg","image_path":"\/sites\/default\/files\/images\/Daryll%20and%20Phil.jpg","image_full_path":"http:\/\/www.tlwarc.hg.gatech.edu\/\/sites\/default\/files\/images\/Daryll%20and%20Phil.jpg","mime":"image\/jpeg","size":323613,"path_740":"http:\/\/www.tlwarc.hg.gatech.edu\/sites\/default\/files\/styles\/740xx_scale\/public\/images\/Daryll%20and%20Phil.jpg?itok=12skhFdN"}}},"media_ids":["663758","663759"],"groups":[{"id":"1292","name":"Parker H. Petit Institute for Bioengineering and Bioscience (IBB)"},{"id":"1188","name":"Research Horizons"},{"id":"1278","name":"College of Sciences"},{"id":"85951","name":"School of Chemistry and Biochemistry"},{"id":"126011","name":"School of Physics"}],"categories":[],"keywords":[{"id":"192250","name":"cos-microbial"},{"id":"187915","name":"go-researchnews"},{"id":"187423","name":"go-bio"},{"id":"985","name":"mRNA"},{"id":"191727","name":"mRNA therapies"},{"id":"186924","name":"nebulizer"},{"id":"191728","name":"inhaler"},{"id":"170522","name":"CRISPR"}],"core_research_areas":[{"id":"39441","name":"Bioengineering and Bioscience"}],"news_room_topics":[],"event_categories":[],"invited_audience":[],"affiliations":[],"classification":[],"areas_of_expertise":[],"news_and_recent_appearances":[],"phone":[],"contact":[{"value":"\u003Cp\u003EWriter: \u003Ca href=\u0022mailto:jerry.grillo@ibb.gatech.edu\u0022\u003EJerry Grillo\u003C\/a\u003E\u003C\/p\u003E\r\n","format":"limited_html"}],"email":["jerry.grillo@ibb.gatech.edu"],"slides":[],"orientation":[],"userdata":""}}}