{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T23:44:52Z","timestamp":1790207092306,"version":"4.1.0"},"update-to":[{"DOI":"10.12688\/f1000research.149854.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,9,11]],"date-time":"2024-09-11T00:00:00Z","timestamp":1726012800000}}],"reference-count":30,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2024,9,11]],"date-time":"2024-09-11T00:00:00Z","timestamp":1726012800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NC3R Skills & Knowledge Transfer Grant","award":["NC\/W000970\/1"],"award-info":[{"award-number":["NC\/W000970\/1"]}]},{"name":"Welcome Trust Institutional Translational Partnership Award","award":["2195760\/Z\/19\/Z"],"award-info":[{"award-number":["2195760\/Z\/19\/Z"]}]},{"name":"The UK National Centre for the Replacement, Refinement and Reduction of Animals in Research","award":["NC\/S001131\/1"],"award-info":[{"award-number":["NC\/S001131\/1"]}]}],"content-domain":{"domain":["f1000research.com"],"crossmark-restriction":false},"short-container-title":["F1000Res"],"abstract":"<ns3:p>Chemoprophylactic prevention of veterinary heartworm disease in companion animals, caused by the vector-borne nematode parasite <ns3:italic>Dirofilaria immitis,<\/ns3:italic> is a multi-billion-dollar global market. Experimental use of cats and dogs in preclinical heartworm drug testing is increasing due to evolving drug-resistance to frontline macrocyclic lactones and renewed investment in alternative preventative drug research. We and others recently published data demonstrating proof-of-concept of utilising lymphopenic severe-combined immunodeficient (SCID) or Recombination Activating Gene (RAG)2 deficient mice with additional knockout of the IL-2\/7 receptor gamma chain (\u03b3c) as alternative preventative drug screening research models of dirofilariasis. Here we summarise the current knowledge of candidate immunodeficient mouse models tested, including a comparison of susceptibility using different background strains of mice, different <ns3:italic>D. immitis<\/ns3:italic> isolates, following use of anti-inflammatory treatments to further suppress residual innate immunity, and efficacies achieved against different reference anthelmintics. We supplement this precis with new data on treatment response to the veterinary anthelmintic, oxfendazole, and initial evaluation of <ns3:italic>D. immitis<\/ns3:italic> susceptibility in CB.17 SCID and C57BL\/6 RAG2<ns3:sup>-\/-<\/ns3:sup>\u03b3c<ns3:sup>-\/-<\/ns3:sup> mice. We conclude that in addition to NSG and NXG mice, RAG2<ns3:sup>-\/-<\/ns3:sup>\u03b3c<ns3:sup>-\/-<\/ns3:sup> mice on either a BALB\/c or C57BL\/6 background offer an alternative screening model option, widening access to academic and commercial laboratories wishing to pursue initial rapid <ns3:italic>in vivo<\/ns3:italic> drug screening whilst avoiding potentially unnecessary cat or dog testing.<\/ns3:p>","DOI":"10.12688\/f1000research.149854.2","type":"journal-article","created":{"date-parts":[[2024,9,11]],"date-time":"2024-09-11T14:20:18Z","timestamp":1726064418000},"page":"484","update-policy":"https:\/\/doi.org\/10.12688\/f1000research.crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Current status of immunodeficient mouse models as substitutes to reduce cat and dog use in heartworm preclinical research"],"prefix":"10.12688","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2579-9077","authenticated-orcid":false,"given":"Jessica L","family":"Dagley","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Utami","family":"DiCosty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Crystal","family":"Fricks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdelmoneim","family":"Mansour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott","family":"McCall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John W","family":"McCall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark J","family":"Taylor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2185-5476","authenticated-orcid":false,"given":"Joseph D","family":"Turner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"2560","published-online":{"date-parts":[[2024,9,11]]},"reference":[{"key":"ref29","article-title":"In vivo model for parasitic worm infection and procedures for evaluating antiparasitic compounds, including compounds active against canine heartworm.","author":"D Abraham","year":"2018"},{"key":"ref1","doi-asserted-by":"publisher","DOI":"10.6084\/m9.figshare.25250101.v1","author":"J Dagley","year":"2024","journal-title":"figshare."},{"key":"ref2","doi-asserted-by":"publisher","DOI":"10.6084\/m9.figshare.25690062.v1","article-title":"ARRIVE guidelines. figshare.","author":"J Dagley","year":"2024","journal-title":"Figure."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"514","DOI":"10.1186\/s13071-017-2452-6","article-title":"Heartworm-associated respiratory disease (HARD) induced by immature adult Dirofilaria immitis in cats.","volume":"10","author":"A Dillon","year":"2017","journal-title":"Parasit. 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Methods."}],"container-title":["F1000Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/f1000research.com\/articles\/13-484\/v2\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/f1000research.com\/articles\/13-484\/v2\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/f1000research.com\/articles\/13-484\/v2\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,11]],"date-time":"2024-09-11T14:20:34Z","timestamp":1726064434000},"score":1,"resource":{"primary":{"URL":"https:\/\/f1000research.com\/articles\/13-484\/v2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,11]]},"references-count":30,"URL":"https:\/\/doi.org\/10.12688\/f1000research.149854.2","relation":{"has-version":[{"id-type":"doi","id":"10.12688\/f1000research.149854.1","asserted-by":"subject"}]},"ISSN":["2046-1402"],"issn-type":[{"value":"2046-1402","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,11]]},"assertion":[{"value":"Indexed","URL":"https:\/\/f1000research.com\/articles\/13-484\/v2#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.5256\/f1000research.164362.r299366, Constantin Constantinoiu, James Cook University, Townsville City, Queensland, 19 Jul 2024, version 1, indexed","URL":"https:\/\/f1000research.com\/articles\/13-484\/v1#referee-response-299366","order":0,"name":"referee-response-299366","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Jessica Dagley<\/b>; \n<i>Posted: 29 Jul 2024<\/i>; Thank you for your feedback. We appreciate the time it has taken to review this article and we take onboard your comments in the updated version. Regarding estimates of reduction in cat and dog use for drug screening, whilst it is impossible to precisely define the percentage reduction with each drug development programme situation and methodology varying, we considered one standard approach, generating murine pharmacokinetic (PK) data combined with an in silico prediction of efficacy based on the relationship between PK and in vitro determined pharmacodynamics (PD) using D. immitis L4 generated in mice. This will reduce numbers of animals required for empirical testing in vivo by selecting only compounds predicted to mediate threshold effects and calibrate doses in vivo to negate equivocal efficacy readouts. In tandem, testing empirical efficacy in the new mouse infection model will further reduce the use of cats or dogs, thereby reducing the risk of adverse reaction occurrence in these highly sentient species. In a scenario where traditionally 10 experimental drug regimens would be run in long-term, 6-month dog studies (72 dogs), with potential welfare consequences, this new approach would cut the number to 24 dogs (67% reduction) replaced by short-term, mild procedures in an estimated 48 mice.","URL":"https:\/\/f1000research.com\/articles\/13-484\/v2#referee-comment-12096","order":1,"name":"referee-comment-12096","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.164362.r299364, Timothy G Geary, McGill University, Montreal, Qu\u00e9bec, 19 Jul 2024, version 1, indexed","URL":"https:\/\/f1000research.com\/articles\/13-484\/v1#referee-response-299364","order":2,"name":"referee-response-299364","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Jessica Dagley<\/b>; \n<i>Posted: 29 Jul 2024<\/i>; Thank you for your feedback and comments. We hope we have addressed your points in the updated version and have some comments below:  - While this article was under review, the report by Risch F et al., 2024 was published. We agree this is an important article, which corroborates our data herein, and indicates independent verification of susceptibility to D. immitis isolates in B.6 RAG2-\/-gc mice. Importantly this research also demonstrates that there is no biological barrier to the migration and development of adults within the heart and lung vasculature in mice. We have added to data and discussion highlighting this research within our article.  - We believe the Mizuseki M et al., 2024 report to be less relevant to our report, as it details a microfilarial-specific infusion model, and thus do not incorporate into comparisons within this specific brief report.  - While the discussion around the mode of action of MLs is warranted, we have discussed this in much greater detail within an earlier publication (Marriott et al., 2023). We have therefore referenced this, but due to this being a brief report, will not discuss in greater detail within the text.  - We appreciate the point raised regarding the rat patent; however, we do not deem it appropriate to discuss data within patents filed where data is not yet peer reviewed and published.  - Regarding the mouse patent filed by Boehringer Ingelheim and awarded in Europe (abandoned in USA) based on the work of Hess et al., 2023, we suggest the patent claims are restricted to the NSG model, and a number of emerging alternative immunodeficient mouse lines proven to be susceptible to D. immitis infection should be available for use without restriction in both academia and industry. We have added some discussion regarding this into the main body of text.","URL":"https:\/\/f1000research.com\/articles\/13-484\/v2#referee-comment-12097","order":3,"name":"referee-comment-12097","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.164362.r299367, Qian Han, Hainan University, Haikou, Hainan, 24 Jul 2024, version 1, indexed","URL":"https:\/\/f1000research.com\/articles\/13-484\/v1#referee-response-299367","order":4,"name":"referee-response-299367","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.164362.r299372, Jan \u0160lapeta, The University of Sydney, New South Wales, 05 Aug 2024, version 1, indexed","URL":"https:\/\/f1000research.com\/articles\/13-484\/v1#referee-response-299372","order":5,"name":"referee-response-299372","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"This research was funded by The UK National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3R) Project Grant to JDT and MJT (NC\/S001131\/1), NC3R Skills & Knowledge Transfer Grant to JDT (NC\/W000970\/1), and a Wellcome Trust Institutional Translational Partnership Award (2195760\/Z\/19\/Z, internal award reference - iTPA2212) to JDT. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":6,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}