{"id":9600,"date":"2023-04-30T15:17:09","date_gmt":"2023-04-30T12:17:09","guid":{"rendered":"https:\/\/kenes-exhibitions.com\/biomed2024\/?p=9600"},"modified":"2023-04-30T15:47:56","modified_gmt":"2023-04-30T12:47:56","slug":"the-decade-of-rna-delivery-beyond-the-liver","status":"publish","type":"post","link":"https:\/\/kenes-exhibitions.com\/biomed2024\/?p=9600","title":{"rendered":"The Decade of RNA Delivery \u2013 Beyond the Liver (March 8)"},"content":{"rendered":"\t\t<div data-elementor-type=\"wp-post\" data-elementor-id=\"9600\" class=\"elementor elementor-9600\">\n\t\t\t\t\t\t\t\t\t<section class=\"elementor-section elementor-top-section elementor-element elementor-element-a14002b elementor-section-boxed elementor-section-height-default elementor-section-height-default\" data-id=\"a14002b\" data-element_type=\"section\">\n\t\t\t\t\t\t<div class=\"elementor-container elementor-column-gap-default\">\n\t\t\t\t\t<div class=\"elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-6253ae1\" data-id=\"6253ae1\" data-element_type=\"column\">\n\t\t\t<div class=\"elementor-widget-wrap elementor-element-populated\">\n\t\t\t\t\t\t\t\t<div class=\"elementor-element elementor-element-e94ef10 elementor-widget elementor-widget-text-editor\" data-id=\"e94ef10\" data-element_type=\"widget\" data-widget_type=\"text-editor.default\">\n\t\t\t\t<div class=\"elementor-widget-container\">\n\t\t\t<style>\/*! elementor - v3.12.1 - 02-04-2023 *\/\n.elementor-widget-text-editor.elementor-drop-cap-view-stacked .elementor-drop-cap{background-color:#69727d;color:#fff}.elementor-widget-text-editor.elementor-drop-cap-view-framed .elementor-drop-cap{color:#69727d;border:3px solid;background-color:transparent}.elementor-widget-text-editor:not(.elementor-drop-cap-view-default) .elementor-drop-cap{margin-top:8px}.elementor-widget-text-editor:not(.elementor-drop-cap-view-default) .elementor-drop-cap-letter{width:1em;height:1em}.elementor-widget-text-editor .elementor-drop-cap{float:left;text-align:center;line-height:1;font-size:50px}.elementor-widget-text-editor .elementor-drop-cap-letter{display:inline-block}<\/style>\t\t\t\t<div class=\"block article-meta\"><p><span class=\"palm-block-level\">Published: Mar 08, 2023<\/span>\u00a0<span class=\"palm-block-level\">By Heather McKenzie<\/span><\/p><\/div><div class=\"block fix-text js-fitvid\"><p><img src=\"https:\/\/admin.biospace.com\/getasset\/72e5bd73-5dbd-4b62-8910-fe07412835ce\/?&amp;Test=Test\" alt=\"Pictured: Iris Grossman, Ph.D., chief therapeutics officer, Eleven Therapeutics\/company courtesy\u00a0\" \/><\/p><p><em>Pictured: Iris Grossman, Ph.D., chief therapeutics officer, Eleven Therapeutics\/company courtesy\u00a0<\/em><\/p><p>With the opportunity to treat spades of infectious diseases, cancers and single gene disorders, there is enormous potential in RNA therapeutics. To realize it, however, researchers will need to optimize delivery to on-target cells, minimize exposure to off-target cells and move beyond the liver.\u00a0 \u00a0<\/p><p>Yogev Debbi is co-founder and CEO of Israel-based Mana.bio, which specializes in \u201cbuilding the space shuttle\u201d for RNA and DNA delivery.\u00a0<\/p><p>\u201cThe RNA is the astronaut that needs to get to the space station in order to fix it. But they can\u2019t just walk there. They need a space shuttle with oxygen and seatbelts that can get past the atmosphere. We build space shuttles,&#8221; he told\u00a0<em>BioSpace<\/em>.<\/p><figure class=\"image\"><img loading=\"lazy\" src=\"https:\/\/www.biospace.com\/getasset\/9a8d18b7-6c7f-4b01-a8a2-713c4d75dfca\/\" alt=\"Pictured: Yogev Debbi, CEO, Mana.bio_company courtesy\" width=\"200\" height=\"202\" \/><figcaption>Yogev Debbi<\/figcaption><\/figure><p>The past two decades were all about nucleic acid reading and writing, Debbi said. The next is about delivering DNA and RNA.<\/p><p>Eleven Therapeutics, tri-located in Tel Aviv, Cambridge, U.K. and Boston, marries the oligonucleotide therapeutics revolution and the AI revolution, Iris Grossman, Ph.D., chief therapeutics officer, told\u00a0<em>BioSpace<\/em>.<\/p><p>In order for RNA therapeutics to make it to the clinic, and eventually the market, Grossman said three properties need to be mastered: potency, durability and delivery.\u00a0<\/p><p><strong>Most Effective Route of Delivery?<\/strong><\/p><p>The conjugate class is the ideal route of delivery for RNA, Grossman said.<\/p><p>\u201cIt\u2019s one and the same backbone of your main moiety. As you think about the CMC and all the characterization efforts, you have a single entity as opposed to multiple entities.\u201d<\/p><p>Conjugates also tend to work via a selective receptor mechanism, often composed of small molecules, antibodies and\/or aptamers.\u00a0<\/p><p>Grossman pointed to N-acetylgalactosamine (GalNAc) short interfering RNA\u00a0(siRNA) conjugates as a prime example. According to a 2018\u00a0<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/29792572\/\">review<\/a>\u00a0in\u00a0<em>Nucleic Acid Therapeutics<\/em>, Tris-GalNAc binds to the asialoglycoprotein receptor highly expressed on hepatocytes, resulting in rapid endocytosis. While the exact mechanism is unknown, \u201cSufficient amounts of siRNAs enter the cytoplasm to induce robust, target selective RNAi responses in vivo,\u201d the authors wrote.<\/p><p>The problem, Grossman said, is that very few of these have been discovered. \u201cWe have yet to identify something that is parallel to GalNAc for other tissues.\u201d\u00a0\u00a0\u00a0<\/p><p>In the absence of conjugates, she said LNPs work fine, but there are immunogenicity and cytotoxicity concerns, particularly in the context of frequent repeat dosing for chronic treatment.<\/p><figure class=\"image\"><img loading=\"lazy\" src=\"https:\/\/www.biospace.com\/getasset\/2e5199d8-d27e-4bcc-ae31-208aff6aff8a\/\" alt=\"Pictured: Iris Grossman,CTO, Eleven Therapeutics\/company courtesy\" width=\"200\" height=\"225\" \/><figcaption>Iris Grossman, Ph.D.<\/figcaption><\/figure><p>In terms of expanding the delivery toolbox, Grossman highlighted antibodies and polymers. Another strategy is to add targeting moieties to LNPs to deliver selectively to a certain cell type.<\/p><p><strong>Lungs: The Next Frontier?<\/strong><\/p><p>The lung has become a hot target of late for RNA therapeutics.<\/p><p>Using its AI\/ML-based engine, Mana.bio designed a lipid nanoparticle (LNP)-based delivery system that is able to selectively target the lung, completely bypassing the liver.\u00a0<\/p><p>This system could effectively deliver mRNA to appropriate cells to treat a single-gene disease like cystic fibrosis (CF). To Debbi\u2019s knowledge, this is the first time an LNP delivery system for mRNA has been designed using AI.<\/p><p>Mana.bio is currently looking to collaborate with partners to leverage this delivery technology for the right payload and the right indication, he said. In addition, the company is focused on unlocking the delivery of RNA to other organs.\u00a0\u00a0<\/p><p>Grossman spoke specifically about RNA interference modalities, such as antisense oligonucleotides (ASOs) and siRNAs.<\/p><p>\u201cAll of them show sometimes exquisite genomic selectivity, specificity and effect size, but the biggest barrier is we don\u2019t know how to get them to the target organ,\u201d she said. \u201cVirtually only the liver has been successfully targeted.\u201d<\/p><p>Grossman will lead a session devoted to this challenge at the upcoming\u00a0<a href=\"https:\/\/kenes-exhibitions.com\/biomed2024\/agenda\/\">Biomed Israel<\/a>\u00a0conference entitled, \u201cFacts and Myths on Ex-Liver Delivery of Nucleic Acid Therapeutics and New Horizons to Cure Rare Disorders\u201d.<\/p><p>Eleven is leveraging its AI-based platform to map the chemical space and uncover the structure-activity relationship of RNA molecules.<\/p><p>The company\u2019s proprietary DELiveri platform inserts a genetic circuit into the cell of interest.\u00a0<\/p><p>\u201cIt allows you to both amplify the intensity of the signal but also reduce the background [noise] because it is so selective.\u201d This makes for a very efficient screening engine, she said.<\/p><p>The company then runs a DNA-encoded library within these cells, allowing it to screen hundreds of thousands of entities at once. \u00a0<\/p><p>In\u00a0<a href=\"https:\/\/www.biospace.com\/article\/releases\/eleven-therapeutics-announces-22-million-in-seed-funding\/\">partnership<\/a>\u00a0with the Bill &amp; Melinda Gates Foundation, Eleven is developing broad-acting prophylactics against COVID-19 and the flu. A third indication targets a yet-to-be-named chronic respiratory disease, which is more in-line with the company\u2019s primary focus.<\/p><figure class=\"image\"><img loading=\"lazy\" src=\"https:\/\/www.biospace.com\/getasset\/589352d6-86aa-4c92-b425-f657ce771dff\/\" alt=\"Pictured: Gili Hart, CEO, SpliSense\/company courtesy\" width=\"200\" height=\"200\" \/><figcaption>Gili Hart, Ph.D.<\/figcaption><\/figure><p>45 minutes away, in Jerusalem, SpliSense is leveraging its proprietary technology to deliver an ASO directly to the lungs via inhalation for CF.<\/p><p>The company\u2019s lead asset, SPL84, is intended to treat CF patients carrying the 3849+10 kilobase (Kb) C-&gt;T splicing mutation in the CFTR gene.\u00a0\u00a0\u00a0\u00a0<\/p><p>SPL84 is a \u201cvery small, short, single strand RNA that can enter the cell very easily, very elegantly with no multiplications, with no need for a carrier, no need for any lipid nanoparticles,\u201d Gili Hart, Ph.D., CEO, told\u00a0<em>BioSpace\u00a0<\/em>in a\u00a0<a href=\"https:\/\/www.biospace.com\/article\/vertex-and-splisense-tackle-cf-with-novel-inhaled-mrna-approaches\/?keywords=SpliSense\">previous interview<\/a>.<\/p><p>Stateside, Vertex is developing VX-522, an mRNA therapy designed to treat the underlying cause of CF lung disease. Part of a research collaboration with Moderna, VX-522 is delivered to the lung through inhalation of a CFTR mRNA encapsulated by a lipid nanoparticle.<\/p><p><strong>Targeting the Brain<\/strong><\/p><p>Beyond the lung, RNA therapeutics have potential to treat several neurological diseases.<\/p><p>The blood-brain barrier stands as the greatest challenge to delivery in this space. But progress is being made. Currently approved\u00a0<a href=\"https:\/\/www.tandfonline.com\/doi\/full\/10.1080\/15476286.2021.2021650https:\/www.tandfonline.com\/doi\/full\/10.1080\/15476286.2021.2021650\">RNA-based therapeutics<\/a>\u00a0for neurological diseases include Sarepta Therapeutics\u2019 Exondys 51 (eteplirsen) for Duchenne muscular dystrophy and Biogen\u2019s Spinraza (nusinersen) for spinal muscular atrophy.<\/p><p>Several others are currently in development. Amsterdam-based uniQure is developing\u00a0<a href=\"https:\/\/www.biospace.com\/article\/going-straight-to-the-striatum-aav-gene-therapy-in-huntington-s-disease-\/\">AMT-130<\/a>, which uses a microRNA to reduce the production of mutant HTT in Huntington\u2019s disease. Wave Life Sciences is developing oligonucleotide therapies for Huntington\u2019s, ALS and frontotemporal dementia.\u00a0<\/p><p>RNA therapeutics also have potential in diseases like Parkinson\u2019s or Alzheimer\u2019s, where part of the biology is clear.<\/p><p>As Debbi said, \u201cYou first need to design the astronaut.&#8221;\u00a0<\/p><p><em>\u00a0*The Biomed Israel conference facilitated meetings with the aforementioned companies at their labs and offices.<\/em><\/p><\/div>\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t\t\t\t\t\t\t<\/div>\n\t\t<\/section>\n\t\t\t\t\t\t\t<\/div>\n\t\t","protected":false},"excerpt":{"rendered":"<p>Published: Mar 08, 2023\u00a0By Heather McKenzie Pictured: Iris Grossman, Ph.D., chief therapeutics officer, Eleven Therapeutics\/company courtesy\u00a0 With the opportunity to treat spades of infectious diseases, cancers and single gene disorders, there is enormous potential in RNA therapeutics. To realize it, however, researchers will need to optimize delivery to on-target cells, minimize exposure to off-target cells [&hellip;]<\/p>\n","protected":false},"author":2,"featured_media":9664,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":[],"categories":[14],"tags":[],"acf":[],"_links":{"self":[{"href":"https:\/\/kenes-exhibitions.com\/biomed2024\/index.php?rest_route=\/wp\/v2\/posts\/9600"}],"collection":[{"href":"https:\/\/kenes-exhibitions.com\/biomed2024\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/kenes-exhibitions.com\/biomed2024\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/kenes-exhibitions.com\/biomed2024\/index.php?rest_route=\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/kenes-exhibitions.com\/biomed2024\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=9600"}],"version-history":[{"count":6,"href":"https:\/\/kenes-exhibitions.com\/biomed2024\/index.php?rest_route=\/wp\/v2\/posts\/9600\/revisions"}],"predecessor-version":[{"id":9665,"href":"https:\/\/kenes-exhibitions.com\/biomed2024\/index.php?rest_route=\/wp\/v2\/posts\/9600\/revisions\/9665"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/kenes-exhibitions.com\/biomed2024\/index.php?rest_route=\/wp\/v2\/media\/9664"}],"wp:attachment":[{"href":"https:\/\/kenes-exhibitions.com\/biomed2024\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=9600"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/kenes-exhibitions.com\/biomed2024\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=9600"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/kenes-exhibitions.com\/biomed2024\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=9600"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}