The One Health Initiative and Its Impact on Drug Development
The One Health concept is a worldwide strategy for expanding interdisciplinary collaborations and communications in all aspects of health care for humans, animals, and the environment. The goal of this initiative is to improve the lives of all species through knowledge integration (www.onehealthinitiative.com/about.php). The strength of the One Health concept is evidenced by the upsurge in articles involving translational research and the growth of translational research groups within veterinary and medical schools. There also are information databases that describe the genes associated with various diseases across human and preclinical (animal) species (e.g., www.Qiagen.com).
The lifespan of companion animals has been increased, leading to the need for long-term treatment of chronic diseases and the onset of age-associated degenerative conditions that parallel those observed in people. Similarly, there are a wide range of shared naturally occurring diseases in dogs and people including arthritis, spinal cord injuries, hemophilia, cleft palate, lysosomal storage disease, inflammatory bowel disease, and several cardiomyopathies. Interestingly, because of a naturally occurring frameshift mutation in the NKX2-8 gene that was shown to cause neural tube defects in Weimaraners, researchers examined and identified rare NKX2-8 missense mutations that were significantly overrepresented in a cohort of 149 human patients with spina bifida, suggesting its role in the pathogenesis of this disease.1
These similarities have resulted in a new term, “zoobiquity,” that reflects efforts to explore how human and nonhuman animal commonalities can be used to diagnose, treat, and heal patients of all species (www.zoobiquity.com). Recognizing that animals and humans share many of the same diseases, the challenge is identifying constraints associated with the translation of scientific and medical/therapeutic information across species lines. This includes exploring commonality of disease (etiology and expression), comparison of genetic and epigenetic regulators, and the development of therapies and delivery systems that can be safely and efficiently employed to achieve effectiveness across species lines. This effort has led to a movement to enhance communication between experts in laboratory science and clinical medicine for the purpose of developing novel therapeutics to prevent, diagnose, and treat disease.
In the past, the focus has been on the use of animal models that are based upon induced diseases. Such preclinical studies often prove to be poor predictors of therapeutic outcomes in human clinical trials.1A problem associated with these models is that the disease progression and etiology may be markedly different from that of naturally occurring disease. Examples of reasons for this failure include the following:2–5
- Animal stress: this can include “contagious anxiety,” in which a fight or flight reaction is induced by animal awareness of procedures conducted on their cohorts. In fact, stress can cause inflammatory conditions that can alter intestinal permeability (i.e., increase leakiness) and neurochemistry.
- Organ structure, which leads to differences in the disease targets.
- For example, human pancreatic islet cells are critical to the development of human diabetes, which is very different from that of rodents, leading to difficulty in extrapolating data generated in the rodent diabetic animal model.
- Another example is the model for human stroke, which often relies on the clamping of blood vessels in the animal model. This method of stroke induction does not resemble the clot or plaque-induced perfusion failure that occurs in humans. Therefore, it is not surprising that >150 stroke drugs found to be effective for stroke in animal models failed to reproduce similar positive therapeutic effects in humans.
- Gene expression of genetically altered animals may have different expression characteristics compared with that of humans. This can lead to potentially misleading experimental results
Thus, we are often left with data that are more closely aligned with that of the animal model of the disease than of the actual human disease.
A hub of this type of synergistic collaboration is the University of Pennsylvania Veterinary Clinical Investigations Center. On their website (http://research.vet.upenn.edu/TranslationalResearch/tabid/4413/Default.aspx), they provide the following list of advantages associated with the study of human diseases in companion animals:
- The conditions can be naturally similar biologically, histologically, and in clinical course.
- Since the disease is not induced, complex and sometimes unexpected tissue interactions can be studied.
- Many diseases are the consequence of complex interactions with environmental factors; therefore, it is relevant that pets share a common environment with people.
- Heterogeneity and diversity of the pet population are more similar to people than rodent models.
- Comparative genomic analysis suggests significant similarity between canine and human lineage in such things as nucleotide divergence and rearrangements.
- Sampling is easier in companion animals compared with rodents.
- Diagnostic and monitoring technologies comparable to human patients are used in veterinary patients.
- The physiology of the dog is such that it responds to and metabolizes drugs in a comparable way to humans, which is why dogs and cats are routinely used for pharmaceutical and toxicological studies.
- Treating naturally occurring disease does not attract the ethical dilemmas seen with experimentally induced disease.
- Data collected is useful both as clinical data for veterinary patients and preclinical data for human patients.
The translational research team at the University of Pennsylvania are bridging the gap between bench and bedside by conducting clinical trials with client-owned dogs and cats. Conventionally, new medical advancements move from experiments with laboratory animals, such as mice, rats, and pigs, directly to human clinical trials. However, through the use of client-owned dogs and cats, scientists, veterinarians, and physicians acquire an appreciation of the outcome of therapeutics in patients whose day-to-day lives more closely resemble our own. While laboratory animals live in a very controlled setting, our pets live in our homes, sometimes eat what we eat, and experience the environment in a similar way that we do. Not only does translational medicine in the veterinary setting benefit the pets we aim to treat, but it also brings us one step closer to treating humans with comparable disease processes.
Another hub of translational activity is the University of Missouri–Columbia, where they are bridging potential therapeutics for shared diseases such as naturally occurring Duchene muscular dystrophy (DMD) in dogs and people.6 DMD is a genetic defect that leads to the replacement of damaged muscle tissue with fibrous, fatty, or boney tissues, leading to the loss of muscular function. It appears to be associated with to a gene mutation that disrupts the production of dystrophin. The absence of dystrophin starts a chain reaction that eventually leads to muscle cell degeneration and death. A homologous disease to DMD exists in dogs. Owing to its size, it is impossible to deliver the entire gene with a gene therapy vector. However, scientists were able to develop a miniature version of this gene (a microgene) that protected all muscles in the body of diseased dogs and humans. The dogs were injected with the virus when they were two to three months old and just starting to show signs of DMD. As reported, at six to seven months old the dogs continued to develop normally. This microgene will soon be used in humans.
Translational research reaches beyond animals that express diseases and segues into exploring why some animal species do not get certain diseases. For example, Peto’s paradox is a term applied to efforts to understand why certain species such as whales or elephants, which have 1,000-fold and 100-fold more cells than humans and a long lifespan, do not exhibit a higher cancer risk than humans. The observation that the amplification of certain suppressor genes, such as TP53, occur in these “cancer immune” species may help to explain the absence of the correlation between size, lifespan, and cancer risk.7It appears that in elephants, TP53 may be related to an increased apoptotic response following DNA damage.8
In addition to therapies, companion animals provide an opportunity to develop and refine diagnostic tests. State-of-the-art diagnostic tools such as immunohistochemistry, molecular diagnostics, and advanced imaging modalities are part of the diagnostic arsenal in veterinary medicine. Similarly, delivery of advanced therapeutic regimens may include organ transplantation, transfusion medicine, minimally invasive and reconstructive surgery, and advanced chemotherapy and radiation protocols.1
Companion animals also develop spontaneous neoplasms that are effectively 100% homologous to those seen in people. In combination with the dog’s shorter lifespan and rapid disease progression, this natural model of disease provides a tremendous opportunity to develop parallel treatments in people and dogs. This is in contrast to the rodent cancer models, whose successful translation of therapeutics to human clinical trials is less than 80%. It also appears that canine and human cancers are influenced by age and environment. Furthermore, dog tumors are histologically similar to human cancers, frequently showing the same tumor oncogenes and suppressor genes.9
From a formulation development perspective, interspecies extrapolation of drug product pharmacokinetics and drug product performance should typically proceed with caution owing to known physiological differences that can influence in vivo product performance.10Such extrapolations can be particularly challenging when bridging between rodent models and humans. Altered drug partitioning into the site of action can occur in the presence of disease, but the use of naturally occurring diseases rather than rodent models can improve predictions of drug delivery to the site of action. Accordingly, the One Health initiative may reduce many of the uncertainties associated with interspecies extrapolations.
In our second article in this series, we will provide further discussion of the commonality of cancer and cancer treatments in dogs and people.
- Kol, A, Arzi, B, Athanasiou, KA, Farmer, DL, Nolta, JA, Rebhun, RB, Chen, X, Griffiths, LG, Verstraete, FJ, Murphy, CJ, Borjesson, DL. Companion animals: Translational scientist’s new best friends, Sci. Transl. Med. 7(308):308ps21 (2015).
- Akhtar, A, Pippin, JJ, Sandusky, CB. Animal models in spinal cord injury: A review, Rev. Neurosci. 19:47-60 (2008).
- Akhtar, A. Why animal experimentation doesn’t work—Reason 1: Stressed animals yield poor data, www.huffingtonpost.com/aysha-akhtar/ animal-experimentation_b_3676678.html (2013).
- Baldwin, A, Bekoff, M. Too stressed to work, New Sci. 194:24 (2007).
- Akhtar, A. Why animal experimentation doesn’t work—Reason 2: Animals don’t get human diseases, www.huffingtonpost.com/aysha-akhtar/ animal-testing-diseases_b_3813856.html (2013).
- Yue, Y, Pan, X, Hakim, CH, Kodippili, K, Zhang, K, Shin, JH, Yang, HT, McDonald, T, Duan, D. Safe and bodywide muscle transduction in young adult Duchenne muscular dystrophy dogs with adeno-associated virus, Hum. Mol. Genet. 24(20):5880-5890 (2015).
- Caulin, AF, Graham, TA, Wang, LS, Maley, CC. Solutions to Peto’s paradox revealed by mathematical modelling and cross-species cancer gene analysis, Philos. Trans. R. Soc. Lond. B Biol. Sci. 370(1673) (2015).
- Abegglen, LM, Caulin, AF, Chan, A, Lee, K, Robinson, R, Campbell, MS, Kiso, WK, Schmitt, DL, Waddell, PJ, Bhaskara, S, Jensen, ST, Maley, CC, Schiffman, JD. Potential mechanisms for cancer resistance in elephants and comparative cellular response to DNA damage in humans,
J. Am. Med. Assoc. 314(17):1850-1860 (2015).
9. Cekanova, M, Rathore, K. Animal models and therapeutic molecular targets of cancer: Utility and
limitations, Drug Des., Dev. Ther. 8:1911- 1922 (2014).
10. Martinez, MN. Factors influencing the use and interpretation of animal models in the development of
parenteral drug delivery systems, AAPS J. 13(4):632-649 (2011).
aU.S. Food and Drug Administration, U.S.A.
bZoetis, LLC (formerly Pfizer Animal Health), U.S.A.
This article is in the public domain and not copyrightable. It may be freely reprinted with customary crediting of the source. Controlled Release Society, 2016