Introduction

Rodents play an invaluable role in biomedical research. Approximately 95 percent of all laboratory animals are mice and rats. Reducing reliance on higher-order species, rodents have become the animal model of choice for biomedical researchers because their physiology and genetic make-up closely resembles that of people. Despite certain differences between people and rodents, the similarities are strong enough to give researchers an enormously powerful and versatile mammalian system in which to investigate human disease.

 

The sequencing of rodent genomes has enabled researchers to recreate human diseases in rodents through genetic engineering. Researchers “knock in” or “knock out” disease-related traits in mice and rats, and new technology allows researchers to directly edit the DNA of the rodents[1]. Research with genetically modified mice and rats has led to significant new treatments, cures and therapies and continues to revolutionize science and medicine.

 

Cancer

Rodents have contributed to cancer research for more than a century[2]. Thanks in large part to the growing arsenal of rodent disease models available to researchers, much of our understanding of the development, prevention and curing of cancer comes from research in rats and mice.

 

Some of the most influential cancer drugs on the market trace their origins to discoveries in rodents. As an example, Herceptin, a hugely popular drug for breast cancer that improves long-term survival[3], was developed with mice[4].

 

Rodent models brighten the future of cancer treatments and cures. Starting with research that showed a modified herpes virus could fight tumors in mice[5], the “oncolytic virus” concept developed into a successful clinical trial in melanoma patients in 2013[6]. In recent years, studies with mice and rats have highlighted a variety of exciting potential therapies for cancer, including tiny nanoparticles that deliver toxins to ovarian cancer cells[7], a vaccine to prevent breast cancer[8], and phototherapy that delivers light to destroy deep tumors[9].

 

Alzheimer’s Disease

Rodents have greatly contributed to our understanding of Alzheimer’s Disease (AD), and drugs derived from rodent research may help alleviate the tremendous economic strain of AD, which in the U.S. is projected to reach $1 trillion in costs per year by 2050[10]In fact, rats are the most commonly studied experimental model of neurodegenerative diseases like AD[11]. Aricept, a common pharmaceutical treatment for AD that improves cognition in patients[12], was developed in rats[13], and Namenda, another common treatment, owes its approval for treating Alzheimer’s in part to rat research into neurotoxicity[14].

 

Aricept and Namenda, like other currently available treatments, only treat AD symptoms. Drugs that instead seek to change the course of the disease are now in clinical trial, thanks to studies with rodents. Studies in “knockout” mice showed how the BACE enzyme is critical to the development of the amyloid plaques associated with AD[15], and now a bevy of drugs that inhibit the BACE enzyme are making their way through clinical trials[16]. Also developed with mice, new vaccines that enlist the immune system to remove amyloid plaques are currently in human trials[17].

 

Cardiovascular Disease

Rodents have become widely used as models of cardiovascular diseases such as atherosclerosis[18] and heart failure[19]. In one prominent example, research in a rat model of heart failure led to the widespread clinical use of angiotensin-converting enzyme (ACE) inhibitors in the aftermath of heart attacks, a practice that decreases mortality by as much as 19 percent over the four years following a heart attack18. In addition, after a new statin drug was shown in rats to block an enzyme associated with high cholesterol[20], it went on to become the widely popular cholesterol-lowering drug Crestor, which garnered 22.5 monthly prescriptions in 201423.

 

Rodent research is creating an exciting horizon for cardiovascular disease treatment. Recent research with rats and mice has alerted scientists to the possibility of using growth factors[21] and stem cells[22] to regenerate cardiac tissue after a heart attack. Mouse research has also highlighted a promising future treatment for atherosclerosis — a molecule that lowers cholesterol levels in the blood and dissolves artery-clogging plaques by mimicking the body’s “good” cholesterol[23].

 

Diabetes

Much of our understanding of type 1 and 2 diabetes comes from rodent models[24]. For example, one mouse model helped point the medical world to the realization that environmental factors may strongly influence the development of type 1 diabetes[25].

 

Currently popular treatments for diabetes originated in studies with rodents. The blood sugar-lowering oral drug metformin, one of the most common treatments for type 2 diabetes, was developed with the help of rat models[26]. Lantus, a long-acting form of insulin that treats both types of diabetes and in 2014 generated 10.1 million monthly prescriptions[27], was first tested in rats and mice[28].

 

In the future, rodents may help cure diabetes. For type 1 diabetes, researchers can transform stem cells into insulin-producing pancreas cells, and when transplanted into diabetic mice, these cells cure high blood sugar[29]. For type 2 diabetes, a human growth factor protein has been found to reverse insulin insensitivity in mice[30].

 

Infectious diseases

From viruses to bacteria to protozoa, rodent models have helped researchers study and develop treatments for a wide range of infectious diseases.

 

In the development of antibiotics to fight against bacterial infection, rodents are essential partners. Penicillin, the watershed antibiotic that transformed the course of human medicine, was first tested in mice in 1940 before reaching WWII soldiers and the wider market[31]. Testing with rodents helped make available the modern antibiotics amoxicillin[32] and azithromycin[33], which together garnered a combined 101.5 million prescriptions in 2014 alone[34]. As medical research scrambles to address the growing problem of bacterial resistance to antibiotics, studies with rats helped bring more recent antibiotics like daptomycin[35] and tedizolid phosphate[36] to the treatment of drug-resistant gram-positive bacteria and staph infections, respectively, and research with mice helped select PA-824[37] as a candidate antibiotic to treat drug-resistant tuberculosis.

 

Once an unstoppable killer, HIV infection has become closer to a manageable condition, thanks to research with rodents and other animals. Research with rats[38] helped develop the antiretroviral drug cocktail that can successfully prevent the transmission of HIV from mother to child[39]. Research with mice with “humanized” immune systems helped lead to the first prophylactic treatment for HIV in 2012, Truvada[40]. These humanized mice are aiding researchers in the quest for the Holy Grail of HIV research, a safe and effective HIV vaccine[41].

 

Human medicine would not be where it is today without the incredible contributions of these small yet mighty animals.

 

(Download a Paper-Friendly Copy)

References

[1] Yang H, Wang H, Jaenisch R. Generating genetically modified mice using CRISPR/Cas-mediated genome engineering. Nat Protoc. 2014;9(8):1956-68.

[2] How and Why Mouse Cancer Models are Used. Electronic Models Information, Communication, and Education and the National Cancer Institute website. http://emice.nci.nih.gov/aam/mouse/how-and-why-mouse-cancer-models-are-used Accessed May 14, 2015.

[3] Paddock C. Herceptin for HER2-positive breast cancer improves long-term survival. Medical News Today. http://www.medicalnewstoday.com/articles/287021.php Updated December 16, 2014. Accessed May 14, 2015.

[4]Baselga J, Norton L, Albanell J, Kim YM, Mendelsohn J. Recombinant humanized anti-HER2 antibody (Herceptin) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts. Cancer Res. 1998;58(13):2825-31.

[5] Liu BL, Robinson M, Han ZQ, et al. ICP34.5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumour properties. Gene Ther. 2003;10(4):292-303.

[6]McBride R. Amgen scores PhIII success with BioVex virus against melanoma. FierceBiotech. http://www.fiercebiotech.com/story/amgen-scores-phiii-success-biovex-virus-against-melanoma/2013-03-19 March 19, 2013. Accessed May 14, 2015.

[7] Huang YH, Zugates GT, Peng W, et al. Nanoparticle-delivered suicide gene therapy effectively reduces ovarian tumor burden in mice. Cancer Res. 2009;69(15):6184-91.

[8] Jaini R, Kesaraju P, Johnson JM, Altuntas CZ, Jane-wit D, Tuohy VK. An autoimmune-mediated strategy for prophylactic breast cancer vaccination. Nat Med. 2010;16(7):799-803.

[9] Kotagiri N, Sudlow GP, Akers WJ, Achilefu S. Breaking the depth dependency of phototherapy with Cerenkov radiation and low-radiance-responsive nanophotosensitizers. Nat Nanotechnol. 2015;10(4):370-9.

[10] Alzheimer’s Association. 2015 Alzheimer’s Disease Facts and Figures. Alzheimer’s & Dementia 2015;11(3)332+.

[11] Braidy N, Muñoz P, Palacios AG, et al. Recent rodent models for Alzheimer's disease: clinical implications and basic research. J Neural Transm. 2012;119(2):173-95.

[12] Rogers SL, Doody RS, Mohs RC, Friedhoff LT. Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group. Arch Intern Med. 1998;158(9):1021-31.

[13] Kawashima K, Sato A, Yoshizawa M, Fujii T, Fujimoto K, Suzuki T. Effects of the centrally acting cholinesterase inhibitors tetrahydroaminoacridine and E2020 on the basal concentration of extracellular acetylcholine in the hippocampus of freely moving rats. Naunyn Schmiedebergs Arch Pharmacol. 1994;350(5):523-8.

[14] Greenamyre JT, Maragos WF, Albin RL, Penney JB, Young AB. Glutamate transmission and toxicity in Alzheimer's disease. Prog Neuropsychopharmacol Biol Psychiatry. 1988;12(4):421-30.

[15] Menting KW, Claassen JA. β-secretase inhibitor; a promising novel therapeutic drug in Alzheimer's disease. Front Aging Neurosci. 2014;6:165.

[16]Lilly Joins AstraZeneca to Co-Develop BACE Inhibitor for Alzheimer’s. Genetic Engineering & Biotechnology News. September 16, 2014.

[17] Lambracht-washington D, Rosenberg RN. Advances in the development of vaccines for Alzheimer's disease. Discov Med. 2013;15(84):319-26.

[18] Zaragoza C, Gomez-guerrero C, Martin-ventura JL, et al. Animal models of cardiovascular diseases. J Biomed Biotechnol. 2011;2011:497841.

[19] Patten RD, Hall-porter MR. Small animal models of heart failure: development of novel therapies, past and present. Circ Heart Fail. 2009;2(2):138-44.

[20] McTaggert et al. Am J Cardiol. 2001 Mar 8;87(5A):28B-32B.

[21] D'uva G, Aharonov A, Lauriola M, et al. ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation. Nat Cell Biol. 2015;17(5):627-38.

[22] Ellison GM, Vicinanza C, Smith AJ, et al. Adult c-kit(pos) cardiac stem cells are necessary and sufficient for functional cardiac regeneration and repair. Cell. 2013;154(4):827-42.

[23] Zhao Y, Black AS, Bonnet DJ, et al. In vivo efficacy of HDL-like nanolipid particles containing multivalent peptide mimetics of apolipoprotein A-I. J Lipid Res. 2014;55(10):2053-63.

[24] King AJ. The use of animal models in diabetes research. Br J Pharmacol. 2012;166(3):877-94.

[25] Leiter, EH. The NOD Mouse: A Model for Analyzing the Interplay Between Heredity and Environment in Development of Autoimmune Disease. ILAR J. 1993:35 (1): 4-14.

[26]Dronsfield A, Ellis P. Drug discovery: metformin and the control of diabetes. Education in Chemistry. 2011;185–7.

[27] Brooks M. Top 10 Most Prescribed, Top-Selling Drugs. WebMD. http://www.webmd.com/news/20140805/top-10-drugs August 5, 2015. Accessed May 14, 2015.

[28] Stammberger et al. Int J Toxicol. 2002 May-Jun;21(3):171-9.

[29] Pagliuca FW, Millman JR, Gürtler M, et al. Generation of functional human pancreatic β cells in vitro. Cell. 2014;159(2):428-39.

[30] Suh JM, Jonker JW, Ahmadian M, et al. Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer. Nature. 2014;513(7518):436-9.

[31] Penicillin. Understanding Animal Research. http://www.understandinganimalresearch.org.uk/why/human-health/penicillin/ Updated November 18, 2014. Accessed May 14, 2015.

[32] Bodey GP, Nance J. Amoxicillin: in vitro and pharmacological studies. Antimicrob Agents Chemother. 1972;1(4):358-62.

[33] Girard AE, Girard D, English AR, et al. Pharmacokinetic and in vivo studies with azithromycin (CP-62,993), a new macrolide with an extended half-life and excellent tissue distribution. Antimicrob Agents Chemother. 1987;31(12):1948-54.

[34]Medicines Use and Spending Shifts: A Review of the Use of Medicines in the U.S. in 2014. IMS Institute for Healthcare Informatics. April 2015.

[35] Eliopoulos GM, Willey S, Reiszner E, Spitzer PG, Caputo G, Moellering RC. In vitro and in vivo activity of LY 146032, a new cyclic lipopeptide antibiotic. Antimicrob Agents Chemother. 1986;30(4):532-5.

[36] Bae SK, Yang SH, Shin KN, Rhee JK, Yoo M, Lee MG. Pharmacokinetics of DA-7218, a new oxazolidinone, and its active metabolite, DA-7157, after intravenous and oral administration of DA-7218 and DA-7157 to rats. J Pharm Pharmacol. 2007;59(7):955-63.

[37] Lenaerts AJ, Gruppo V, Marietta KS, et al. Preclinical testing of the nitroimidazopyran PA-824 for activity against Mycobacterium tuberculosis in a series of in vitro and in vivo models. Antimicrob Agents Chemother. 2005;49(6):2294-301.

[38] Young SD, Britcher SF, Tran LO, et al. L-743, 726 (DMP-266): a novel, highly potent nonnucleoside inhibitor of the human immunodeficiency virus type 1 reverse transcriptase. Antimicrob Agents Chemother. 1995;39(12):2602-5.

[39] Antiretroviral drugs for treating pregnant women and preventing HIV infection in infants. World Health Organization HIV/AIDS Programme. 2010.

[40] Denton PW, Estes JD, Sun Z, et al. Antiretroviral pre-exposure prophylaxis prevents vaginal transmission of HIV-1 in humanized BLT mice. PLoS Med. 2008;5(1):e16.

[41] Tager AM, Pensiero M, Allen TM. Recent advances in humanized mice: accelerating the development of an HIV vaccine. J Infect Dis. 2013;208 Suppl 2:S121-4.