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The SCHER opinion states:
Only few candidate pharmaceuticals are actually tested on primates
Source: Understanding animal research3.1.2.Selection of non-rodent species for toxicological studies and rationale for using NHPs
Safety testing of chemicals is performed by a combination of many different approaches including animal experimentation. Whereas for industrial chemicals, toxicity testing in non-rodents is not required, inclusion of a non-rodent species is required in the safety assessment of pharmaceuticals. However, most of the safety testing for pharmaceuticals is also performed in rodents. Furthermore, non-animal methods play an important role in candidate drug selection and selection for further testing in animals, as well as for the selection of the animal species (Sietsema and Schwen, 2007). It needs to be noted that only a very small percentage of pharmaceuticals initially selected for further development are finally introduced into the marketplace since they fail on the bases of lack of efficacy or unwanted toxic effects predicted by the safety testing. While safety testing of new pharmaceuticals and other medical products represents one of the major uses of NHPs, only few candidate pharmaceuticals are actually tested in NHPs. Normally, there is no routine requirement for the use of NHPs as a second species.
Animal safety testing of pharmaceuticals is intended to safeguard human subjects used in the clinical trial studies through risk assessment based on the results of animal experiments. The Declaration of Helsinki* is a set of ethical principles developed by the World Medical Association (WMA) for the medical community regarding human experimentation. It states that the wellbeing of the human subject should take precedence over the interests of science and society.
International regulatory authorities including the European regulatory authorities therefore require that the safety of a new medicinal product is supported by a variety of non-clinical data prior to the start of clinical studies. The scope of testing is regulated in the EU by Council Directive 2001/83/EEC and its amendments.
As a consequence, the European Medicines Agency (EMEA) Committee for Medicinal Products for Human Use (CHMP) prepares scientific guidelines, in a global harmonisation process in the framework of the International Committee for Harmonization (ICH), to help applicants prepare marketing-authorisation applications for medicinal products for human use. The safety guidelines are written to ensure that duplication of studies is not required for various regions in the world. These guidelines also indicate that the non- clinical studies are performed in “relevant species”, and that pivotal studies for risk assessment of pharmaceuticals, such as the repeated dose toxicity testing, have to be performed in two species, one of which must be a non-rodent.
In Europe, medical products tested in NHPs over recent years include all classes of pharmaceuticals and the main reason is the fact that no other species showed the same primary pharmacodynamic response. NHPs are also selected when they represented a well-established model for pharmaceuticals of that class or are the most relevant species for detecting known side effects. In addition, NHPs are used in testing because of recommendations from regulatory agencies including the US FDA, the EMEA, the Japanese authorities, and the WHO. For vaccines, some European Pharmacopoeia monographs, the US Code of Federal regulations (US CFR) and WHO monographs require that bulk and/or seed lots of live viral vaccines are tested for safety (i.e. neurovirulence) or potency on defined numbers of NHPs.
The species for toxicity testing selected based on its similarities to humans with regard to pharmacology and pharmacokinetics, including biotransformation and in certain cases also where anatomical similarities are essential. The use of a non-rodent species for the characterisation of new medicinal products aims at limiting the uncertainty in the extrapolation process fromanimaltoxicity data to the humansituation. Such uncertainties are species variation, scaling from small, short-lived animals to large, long- lived species, and use of a homogeneous animal population (NCB, 2005). Dogs are most frequently used as the non-rodent species, and NHPs are only used when testing is considered essential for safety assessment.
The CHMP has defined criteria on the demonstration of relevance of an animal species to predict human safety (EMEA/CHMP/SWP/28367/07).
The scientific requirements specific to the substance include:
- Presence of the required pharmacodynamic binding site and response
- Similarity to human toxicity or pharmacokinetic profile based on in vitro data or prior experience with related compound(s) of the same class
- Similarity to human in aspects of anatomy or physiology of specific organ systems
- Indication for the need of an additional species to investigate a toxic effect or the effects of a significant metabolite in humans which is not produced in the original non-rodent species
The ABPI and Home Office (2002)* gave additional specific recommendations on the selection and justification of the relevance of an animal species for safety testing:
- Use of a well characterised species may be quicker and require fewer animals
- Unknown and contradictory neurophysiological sensitivity (meant to reflect differences in suffering, harm etc) of the species (e.g. dog vs. pig)
- Public perception (e.g. dogs and other pets)
- Limited availability of new pharmaceutical in early stages requesting small size animal to allow fast development of new pharmaceutical for serious medical condition.
According to all these recommendations, NHPs should only be used when it is scientifically demonstrated that none of the other non-rodent species commonly used in safety testing is appropriate for the purpose of the study.
To illustrate, safety testing in the NHP may be preferred over that in other mammalian species in the following cases:
- Due to the similar menstrual cycle and the anatomy and physiology of the mammary gland of NHP females and human females, NHPs (cynomolgus monkeys) are the more pertinent species in term of predictivity of relevant reproductive effects (Buse et al., 2003; Cline, 2007; Luetjens et al., 2005) and are therefore often chosen as non-rodent species for classes of compounds, which are expected to provoke effects on the female genital organs.
- Regarding the ocular system, the retina of NHP and man show some unique features (e.g. both NHPs and humans have a macula lutea/fovea) not found in other mammals (Stone and Johnston, 1981) and therefore NHPs represent a more relevant model of specific ocular effects for discovery and development of new pharmaceuticals as compared with other species.
- NHPs are less susceptible to vomiting than dogs. Thus, pharmaceuticals with an emetic effect in the dog may be tested in the monkey (Weber, 2005). Vomiting does not only limit exposure of the pharmaceutical administered, but is also a major hurdle to accurately characterise early effects on behaviour and on the cardiovascular system.
- The blood coagulation system of NHP is more similar to humans than that of any other species (Abildgaard et al., 1971; Lewis, 1996) and thus, NHP are often the most suited model for humans to assess potential toxicity of coagulation factors and anti-coagulation agents.
- NHPs are the most appropriate animals to characterise safety of many biotechnology-derived pharmaceuticals, especially monoclonal antibodies, since the most relevant species for testing is selected based on species-specific aspects of the immune system. Monoclonal antibodies are highly specific to their targets and accurate prediction of ‘on-target’ effects requires testing in a species which shows cross-reactivity, thus frequently requiring testing in NHPs as only species cross-reacting with humanised monoclonal antibodies (APBI-NC3Rs,2006; Weatherhall, 2006); (Chapman et al., 2007).
- Recent regulatory guidance for assessing human drug abuse of new central nervous system (CNS) pharmaceuticals may further increase the need for testing in NHPs, since all CNS-active pharmaceuticals with properties indicating stimulant, depressant, hallucinogenic, or mood-elevating effects require an evaluation of abuse liability (EMEA/CHMP/ SWP/94227/2004). Whilst the rat is in principle acceptable for self-administration studies in the EU, NHPs are preferred in Japan.
- Historically, non-primate species have been used for reproductive toxicity studies, generally mice, rats and rabbits. However, rodents and rabbits are not necessarily the most accurate predictor of teratogenicity or reproductive toxicity in humans due to differences in placental anatomy and number of foetuses. In addition, they are not suitable models for all aspects of human reproductive toxicity, specifically for the investigation of agents suspected or known to interfere with the menstrual cycle. In such cases, NHPs may be more predictive for human toxicity. The male cynomolgus is also a good model of male fertility in specific cases (Ehmcke et al., 2006; Millar et al., 2000). Rodents can also not be used to assess the safety of novel hormonal intrauterine devices or cognitive dysfunction associated with the menopause (Schlatt et al., 2008; Wistuba and Schlatt, 2002). The need for NHPs in specific aspects of reproductive toxicity testing is exemplified with lenalidomide, a compound recently approved to treat multiple myeloma. Lenalidomide is structurally related to thalidomide, a known human teratogen that caused severe birth defects during the late 1950s and early 1960s when given to pregnant women suffering from morning sickness. In rodent reproductive toxicity studies, lenalidomide did not induce teratogenic effects. In rabbits, although reproductive toxicity was evident, no limb abnormalities were observed, while in a group of animals treated with high doses of thalidomide, there was a significant incidence of multiple limb abnormalities (Revlimid, EPAR). Studies with thalidomide in monkeys have shown high similarity in teratogenicity to that documented in humans, both in terms of doses and types of malformation (Hendrickx et al., 1983). Since the Cynomolgus monkey appeared highly relevant for humans, both with regards to pharmacological and toxicological effects of lenalidomide, reproductive toxicity testing in NHPs was requested by the CHMP. These studies showed that lenalidomide produced malformations (short limbs, bent digits, wrist and/or tail, supernumerary or absent digits) in the offspring of primates that received the drug during pregnancy. Consequently, lenalidomide is expected to be teratogenic also in humans and specific precautionary measures need to be taken if lenalidomide is to be given to women of child-bearing potential.
The development of therapeutical monoclonal antibodies has resulted in an increased need for primates in reproductive toxicology since the immune system in macaques is much more similar to humans compared with rodents. In addition, the ontogeny of the immune system differs between rodents and primates, including humans, in that the immune system in rodents is less mature at time of birth. Rodent safety testing may therefore miss potential effects in a critical phase of development in uterus.
The need for specific safety and efficacy testing of drugs used in paediatrics in “young” animals may further increase the use of NHPs since the age-dependent development in NHPs is very similar to humans and NHPs may therefore be preferred over rodents as a test species.
Selection of the non-rodent species for safety testing is considering species specificities and also recognizes that toxicity testing in NHPs is not always predictive of all aspects of human toxicity. For example, regarding livertoxicity, the dog may be more representative of human metabolism than NHPs and in general, hepatobiliary toxicity in humans has been poorly predicted from animal studies (Peters, 2005). Although the NHP is the most representative species with regards to several of the aspects of the human immune system, there are important differences in, for example, parts of the T-cell intracellular signalling pathways. This was illustrated in the TGN1412 case which resulted in severe side effects in humans, but induced only a weak signal in NHPs (Waibler et al., 2008). Existing animal models also have limited capability for prediction of certain types of drug allergy in humans (Bala et al., 2005).
Therefore, for a safety assessment of a medical product it is required that all relevant information gathered from a variety of animal and non-animal models including computer-based prediction of biotransformation for a final conclusion based on a weight of evidence approach (Boobis et al., 2008; Doull et al., 2007).
Examples for major new treatment options for debilitating diseases where NHPs have been used in the safety assessment as the best available model for humans due to close similarities in physiology and anatomy are the development of a humanised recombinant antibody to treat severe asthma (EMEA, Xolair), an antibody directly injected into the eye to inhibit vascular endothelial growth factor thus preventing neovascular age-related macula degeneration often resulting in blindness (EMEA, Lucentis) and the approval of prostaglandin analogues in eye drops to decrease intraocular pressure thereby preventing loss of vision in patients with glaucoma (Stjernschantz, 2001).
[*ABPI and Home Office (2002) Non-rodent selection in pharmaceutical toxicology: A ‘Points to Consider’ document, developed by the ABPI in conjunction with the Home Office]
[* Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 29th WMA General Assembly, Tokyo, Japan, October 1975; 35th WMA General Assembly, Venice, Italy, October 1983 ; 41st WMA General Assembly, Hong Kong, September 1989; 48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996; 52nd WMA General Assembly, Edinburgh, Scotland, October 2000; 53th WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 added); 55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added); 59th WMA General Assembly, Seoul, October 2008]
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Section3.1.2 Selection of non-rodent species for toxicological studies and rationale for using NHPs, p.11 -14.
The SCHER opinion states:
3.1.3.Uses of NHPs in research regarding treatment and prevention of infectious diseases
The development of safe and effective intervention strategies against emerging and currently circulating human pathogens, like vaccination and treatment with antibiotics, antivirals and other medicines, are urgently needed. The three major global health threats are HIV, malaria and tuberculosis (TB), but new pathogens, such as the SARS- corona-virus and avian/pandemic influenza viruses, are emerging. In the developing countries, AIDS, malaria and TB are major sources of morbidity and mortality and have a severe impact on the economic burden for affected families (Russel, 2004).
Several vaccines currently used to protect humans against fatal infectious diseases have been developed through studies in NHPs. Before new candidate vaccines can be evaluated for efficacy in humans, their efficacy has to be assessed in animals. For several infections, NHPs are the only animal species susceptible to the infectious agent and proof-of-concept of candidate vaccines can therefore only be studied in these species. As an example, the final confirmation of the efficacy of smallpox vaccines must be performed in NHPs, using exposure to monkeypox (EMEA/CPMP/1100/02). Other infectious agents for which NHPs have been a valuable resource for vaccine research include influenza virus, paramyxoviruses, flaviviruses, arenaviruses, hepatitis E virus, papillomavirus, Mycobacteria, Bacillus anthracis, Helicobacter pylori, Yersinia pestis, and Plasmodium species (Gardner and Luciw, 2008). Furthermore, to understand the mechanisms of protective immune responses induced by candidate vaccines, it is critical to use an animal model in which the immune system closely mimics that of humans. The choice of the animal model for testing new vaccines and drugs will largely depend on the nature of the pathogen. Many human pathogens have co-evolved with their primate hosts for many millions of years, and a process of mutual adaptation of pathogen and host has taken place. For this reason, many studies on pathogenesis and subsequent intervention studies are most effectively carried out in NHPs.
Vaccination studies conducted in rodents are not easily translatable into clinical trial protocols, due to qualitative differences between rodent and human immune systems. Therefore, the validity and the quality of the induced immune response to the vaccine need to be assessed in an animal model that is genetically very close to humans. Safety assessment of the candidate vaccine, which is required before entering into clinical trials, needs also to be performed in NHPs.
The use of NHPs may be necessary for the rapid identification of newly emerging infectious diseases with pandemic potential. For example, studies on NHPs led to a rapid development of the appropriate intervention strategies, which effectively prevented a pandemic spread of the SARS-coronavirus (Osterhaus et al., 2004).
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Section 3.1.3 Uses of NHPs in research regarding treatment and prevention of infectious diseases, p. 14-15.
The SCHER opinion states:
HIV
The spread of HIV/AIDS can probably not be stopped without the use of an easily accessible vaccine. However, the immediate goal is not to develop a 100% effective vaccine, but a vaccine that at least partially protects against HIV infection and also protects against development of AIDS in patients already infected. A 50% effective vaccine given to just 30% of the population, could reduce the number of new HIV infections in the developing world by more than half in 15 years (IAVI, 2006).
Preclinical studies in NHPs play a key role in AIDS vaccine development (Morgan et al., 2008). Vaccine efficacy data are generated from immunised NHPs challenged with either simian immunodeficiency virus (SIV) or chimeric simian/human immunodeficiency (SHIV) virus (Letvin, 2005). Macaques infected by SIV develop clinical signs very similar to those in humans infected by HIV. In addition, the development of the disease in macaques is predictable from the viral load in the blood at early stages of infection (Sato and Johnson, 2007). Mucosal immunity is known to play a critical role in the susceptibility of humans to HIV infection. In this context, NHPs, which are also susceptible to infection via the mucosal route and thus mimic the natural infection in humans, are a unique model that currently cannot be replaced by in vitro systems (Yuki et al., 2007).
In addition to their traditional utilisation to judge vaccine safety and immunogenicity, NHP models are also employed to probe fundamental mechanisms of primate immune system regulation, to investigate pathogenic mechanisms of AIDS, and to optimise immunisation strategies involving novel vaccine vectors (Staprans and Feinberg, 2004).
Animal models can only be validated after successful trials in humans and the determination of correlates of protection. The HIV-vaccines tested to date in phase III trials in humans have failed to achieve the desired protective threshold. Therefore, we cannot at present judge the full validity of the currently used NHP models for vaccine research. However, NHP models yielded data on immune responses to vaccines congruent with clinical data (Makitalo et al., 2004; Sandstrom et al., 2008). This finding suggests that primate models are valuable as adjunctive testing systems to prioritise future therapeutic and vaccine strategies (Haigwood, 2004). In fact, there is now a growing consensus in the field that candidate vaccines should be studied even more thoroughly in NHPs before moving into large and expensive clinical trials (Morgan et al., 2008).
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Section 3.1.3 Uses of NHPs in research regarding treatment and prevention of infectious diseases, p. 15-16.
The SCHER opinion states:
According to WHO (WHO, 2008), approximately one third of the world population was infected with Mycobacterium tuberculosis in 2006, and more than 1.7 million people die from tuberculosis (TB) every year. The current TB vaccine (BCG) was developed at the beginning of the 20th century, and is still the most widely used vaccine worldwide. However, its efficacy is varying. In the last 15 years, new strategies to improve or replace BCG have led to several candidate vaccines being evaluated in human clinical trials. These vaccines are based on the “prime-boost” principle, and have been extensively tested in animals, including NHPs, before clinical trials (Ly and McMurray, 2008).
As for many infectious diseases, there is no ideal experimental animal model for TB, and information has to be gathered from studies in various animal species. NHPs develop pulmonary granulomas in response to Mycobacterium tuberculosis and show an immune response similar to humans. There are differences between macaque species in response to vaccination and protection against infection. Comparative studies in these closely related species are likely to provide insight into mechanisms involved in protection against TB (Langermans et al., 2001).
The mouse and guinea-pig provide important and often complementary answers to TB vaccine questions. Before proceeding to human studies, however, it is necessary to perform confirmatory studies on efficacy in NHPs (Kaufmann, 2000). Only the most promising vaccine candidates are considered for NHP experiments.
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The SCHER opinion states:
In 2005, the WHO/UNICEF reported that approximately 350 to 500 million people were infected with malaria (WHO/UNICEF, 2005). More than one million die from the infection each year; many of them are children under 5 years of age. The challenges to develop a successful vaccine are great, as there are 4 species of malaria that infect people. In addition, during the course of malaria infection, the human host is confronted by four distinct life cycle stages of the parasite. Each of these life stages presents new antigens (targets) to the immune system. Human genetic differences can also affect the level of immunity in response to a vaccine. Therefore, a vaccine against Plasmodium falciparum, the most serious malaria parasite, must account for the genetic diversity of both the parasite and the human host, and provide effective immunity against all different life cycle stages of the parasite.
The owl monkey (Aotus) and the squirrel monkey (Saimiri) are the only species (besides the chimpanzee) that are susceptible to the human malaria parasite and they are used (in very limited numbers) to test the potential efficacy of human malaria vaccines (Gysin et al., 1996; Herrera et al., 2002). The rhesus macaque has also been used to study the immunogenicity of candidate vaccines, without studying protection against infection (Stewart et al., 2006). A candidate vaccine developed with the use of NHPs is now in Phase III studies. Although many challenges have yet to be overcome, the development of an effective malaria vaccine is likely (Dolan and Stewart, 2007).
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Section 3.1.3 Uses of NHPs in research regarding treatment and prevention of infectious diseases, p. 16.
The SCHER opinion states:
Other infectious diseases
As an example of other infectious diseases, hepatitis C virus infects about 170 million people worldwide (WHO, 1999). The search for a vaccine against this disease is complicated by the fact that the only species besides humans that is susceptible to the hepatitis C virus is the chimpanzee. In earlier phases of hepatitis C vaccine development, in vitro techniques and other animal species are often used, and chimpanzees are only used for testing the efficacy of very promising candidate vaccines. Recently, a vaccine capable of eliciting virus-specific immune responses in baboons and genetically altered mice was developed. When testing this vaccine in chimpanzees, a significant immune response to the hepatitis C virus was elicited, and the virus became essentially undetectable in the infected animals for at least a year (Contie, 2007).
In Europe, studies with chimpanzees are not performed, and research groups that are studying this virus must utilise laboratories in USA and other parts of the world to perform the necessary experiments.
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Section 3.1.3 Uses of NHPs in research regarding treatment and prevention of infectious diseases, p. 17.
The SCHER opinion states:
3.1.4.Use of NHP in Neuroscience
Research in neuroscience collects knowledge on how the brain works in healthy human subjects and after disease and injury in humans and in experimental animals, including NHPs. Basic research is required in order to better understand how the brain works normally and in pathological conditions (Editorial, 2008). The main reasons to use NHPs in neuroscience are the close similarities between NHP and human brains in terms of overall anatomy, cellular structure and chemical communication, functional and cognitive abilities, neural circuitry, and in brain injury and diseases. This knowledge is useful, not only to understand effects and consequences of brain and spinal cord damage in humans and to devise therapies, but also help to construct new experimental models in silico and in vitro, and to develop new computational technologies. There is a continuous iteration between basic, translational, and applied medical research in neuroscience (Fitzsimmons et al., 2007; Moritz et al., 2008).
Neural injuries and diseases encompass disorders like epilepsy, cerebrovascular disease, depression, addiction, Alzheimer’s disease and other dementias, Parkinson’s disease, and multiple sclerosis. These diseases have an important impact on society in terms of number of affected humans and their relatives affected (WHO NeuroAtlas, EBC). In 2004, 127 million, or one in three, European citizens were living with a brain disorder at a total cost of €386 billion (EBC, 2008). Brain research received 8% of the life science budget in the European Commission’s Fifth Framework Programme of research (FP5, 1998-2002), and 10% of the FP6 budget (2007-2010), a proportion that is likely to grow (EBC, 2008).
The unique role of NHPs in neuroscience research
Although major advances have been made in past 50 years, our knowledge on human brain function is still limited and the use of NHPs remains crucial for a significant advancement of neurosciences (Weatherhall, 2006).
Much of our current understanding of nerve cell function is based on studies in animals such as the cat, rat and even invertebrates such as squid where brain structure and circuitry is much less complex as compared with humans. However, the organisation of nerve cells in a complex system such as the human brain is more likely be understood by studying a similarly complex primate brain. In fact, only because of recent studies in NHPs, the existence of primate-specific developmental features was discovered (Bystron et al., 2006; Dehay and Kennedy, 2007; Garcia-Cabezas et al., 2008; Letinic et al., 2002; Meyer et al., 2000; Sanchez-Gonzalez et al., 2005; Smart et al., 2002). Moreover, most current human neuroscience research is based on evidence first discovered in NHPs, e.g., the neural bases of working memory (Goldman-Rakic, 1995), dopamine-
based learning (Schultz, 2002), motor function (Georgopoulos, 2000), and mirror systems (Fabbri-Destro and Rizzolatti, 2008; Rizzolatti and Fabbri-Destro, 2008).
Experiments using invasive neurophysiological recordings in NHPs raise some ethical concerns; however, our understanding of the functional organisation of the brain areas involved in vision, sensation, hearing, motor control and cognition in primates and humans has significantly benefited from of such work. An example is the research on primate visual pathways that led to a Nobel Prize in the early 1980s which, as well as elucidating visual centres and the mechanisms in NHPs, went on to discover similar pathways in humans (Rees et al., 2000; Tootell and Taylor, 1995). NHPs currently provide the only model to systematically study the relationships between the activity of a single nerve cell and higher cognitive functions. It is relevant to note, however, that in some instances, such as during brain surgery, neurophysiological recordings can also be made on humans (Alonso-Frech et al., 2006).
Some non-invasive research techniques, such as transcranial magnetic stimulation (TMS) are used both in humans and NHPs, and provide highly relevant information on how the brain works, thus saving invasive studies (e.g. (Ellison et al., 2007). However, TMS can only be used to study human brain areas near the surface of the skull. If deeper areas need to be studied, it will require invasive methods (causing permanent and reversible lesions) in animals, including NHPs.
Motor control is another area where the use of NHPs has been instrumental for basic understanding of the production and control of arm movements (grasping and reaching) leading to brain-computer interface technologies which are of major relevance to help alleviate the consequences of brain lesions and spinal cord injuries (Moritz et al., 2008).
Only small aspects of the complex interactions in the brain can be studied using in vitro techniques. More complex interactions can be studied using brain slices, but this requires the sacrifice of animals. Cell cultures can be used to study synaptic mechanisms and cellular events occurring in single cells. For example, to study the role of neuromodulatory molecules (like dopamine) on a neural network requires the use of intact tissue because the location of receptors on the different cells at different stages of a local network is one of the important keys to understand how the neuromodulation will act on information processing by the network. Such mechanisms have been studied on rodents, in particular rat, brain slices. However, the characteristics of e.g. cortical arrangement of neural networks and distribution of the different dopaminergic receptors within the cortical layers differ greatly from rodents to primates. Although there are evolutionary trends of variation in receptor localisations between primate species, there are drastic changes between rodents and primates. Therefore, conclusions based on in vitro data are limited.
NHP models and treatment of diseases
Pain
The use of animals in pain studies for the basic mechanistic understanding and for the development of therapies is one of the most controversial areas of research, but it has been estimated that chronic pain of moderate to severe intensity occurs in 19% of adult Europeans, seriously affecting the quality of their social and working lives (Breivik et al., 2006). A workshop was recently held to review and discuss the potential and challenges of using ethically conducted studies in human patients and volunteers to replace animals in certain areas in pain research and in the development of new therapies (Langley et al., 2008), and it appeared possible in some areas.
It should be noted that pain research is mainly performed in rodents and very rarely with NHPs. Research on neuropathic (chronic) pain is still a major issue since neither animals nor healthy humans are good models.
Neurochemistry
The study of the neurotransmitters (chemicals transmitting information between neurons), their receptors, transporters and enzyme systems in the human brain is key to understanding normal and pathological brain function, as well as to reveal possible targets for treatment. Basic mechanisms on neurotransmission and neuromodulation can be studied in vitro and in non-primate species (such as rodents and rabbits) (Carlsson, 1993; Vandecasteele et al., 2008). However, due to the large evolutionary distance between humans and rodents, the study of neurotransmitters and related molecules at the level of the entire brain requires research on NHPs. In fact, data on rodents may be misleading as their brain physiology and biochemistry is different from those of NHPs and humans (Bjorklund and Dunnett, 2007; Garrick and Murphy, 1980; Howell and Wilcox, 2002).
Neurological diseases
Brain disorders such as depression, schizophrenia, attention deficit hyperactivity disorder, autism, drug addiction and obsessive compulsive disorders, all involve malfunctioning of the highly developed primate frontal lobes and their interactions with other parts of the brain. This is also true of conditions such as traumatic head injury, Huntington's disease, stroke and some types of dementia, which also involve interactions between multiple systems in the brain (Gil and Rego, 2008; Van Hoesen et al., 2000). Such conditions cannot, or only partially, be reproduced in non-primate species. Even if NHP are not ideal models for the above conditions, their complex brains make them more suitable to further advance knowledge than non-primate species (Yang et al., 2008).
NHPs have been used to investigate neurological diseases occurring in human neonates. For example, rhesus can be a surrogate model for asphyxia insults at birth and accurately reflects the mechanisms and neuropathology seen in human newborns suffering from this condition. More recently, a premature baboon model developed for evaluation of bronchopulmonary dysplasia has been applied to the investigation of cerebral development and injury, revealing a high similarity in neuropathology to the premature human infant (Inder et al., 2005).
Stroke research does not use large numbers of NHPs, but the importance of their availability as a research tool is significant. An example of NHP use in stroke research was the development of the drug NXY-059 (Marshall et al., 2003) that had significant effects and reduce functional disability following ischemic stroke. The NXY-059 studies in NHPs were regarded as crucial in designing the SAINT trials in humans. While the SAINT I clinical trials showed some promise, the SAINT II trials revealed no significant effects. The review procedures from animal trials to clinical studies have been published and suggested a need, not to change the model, but the criteria for publication, evaluation and use of animal testing (Macleod et al., 2008).
Important efforts are being made to develop better models of psychiatric disease by screening large populations of animals to detect the presence of a similar disease in NHPs. In the study of depression, simple tests for anti-depressant-like activity of pharmacological substances are often based on known classes of therapeutically successful existing anti-depressant agents, but investigators have also endeavoured to reproduce factors in the laboratory that are believed to initiate depression in humans. Studies on large macaque colonies show that some individuals, in particular those of low social rank, express behavioural signs comparable with some human depression syndromes. Neuroimaging has shown activity deficits in NHPs, comparable with those in humans, thereby supporting their use for further neurobiological characterisation and modelling (O'Neil and Moore, 2003).
A model of Parkinson’s disease (PD) in NHPs has been highly valuable in studying its pathophysiology (Beal, 2001; Boulet et al., 2008; Emborg, 2004; Hamani and Lozano, 2003; Mounayar et al., 2007). The application of deep-brain stimulation (DBS) in humans with Parkinson’s disease derives from experiments in a NHP model showing that destruction or high-frequency stimulation of certain areas in the brain reversed Parkinsonian symptoms. Over 40,000 patients have now been treated with DBS worldwide, and there are 160 DBS centres in Western Europe. In addition, DBS is showing promise in other brain conditions such as drug resistant cases of depression, obsessive compulsive disorders, and Tourette’s syndrome. However, there are still significant cases of unpredicted adverse effects, and numerous patients who are not suitable for DBS show there is still a need for further research such as advancements in DBS, local delivery of neural active substances, the application of neurotrophins and stem cells, gene therapy, and molecular neurosurgery (Hamani and Lozano, 2003).
Stem cell technology, like induced pluripotent stem cells, opens the possibility to use somatic cells of an individual to repair his own tissue, thereby removing some of the ethical issues concerning embryos and the problem of rejection. These technologies are being currently developed for the repair of brain tissue in Parkinsons, Huntingtons, in stroke and in spinal cord and brain injuries, but will likely require safety and efficacy testing in NHPs (Brundin et al., 2008; Chen and Palmer, 2008; Roh et al., 2008).
Research on sensory and motor systems has led to the new field of neuroprosthetics to restore the severe loss of sensory abilities or movement capabilities in paralysed patients (Weatherhall, 2006). The development of brain machine interfaces (BMI) has much benefited from neurophysiological experiments in NHPs showing that it is possible to use natural brain cortical neural activity to drive computers, robots, and artificial limbs, to restore volitional control of movement to paralysed limbs, and/or to compensate for perceptual deficits (Fitzsimmons et al., 2007; Moritz et al., 2008).
New fields in neurosciences
New fields and techniques to assess brain structure and function, such as Magnetic Resonance Imaging (MRI, now routinely used for diagnosis in humans), and functional MRI (fMRI), are rapidly developing and increasingly employed in human clinical and experimental studies. Even though they are powerful means to study brain function, these techniques also have important limitations as they only measure blood flow, which is an indirect measure of neuronal activity (Logothetis, 2008; Vanzetta, 2006; Vanzetta and Grinvald, 2008). Other valuable non-invasive techniques, that provide useful information on how the brain works, include multichannel electroencephalography (EEG) and magneto-encephalography (MEG), both of which have a better temporal resolution than fMRI, but still have poor spatial resolution. Thus, fundamental research, at the level of single neuron activity (that may be invasive), is still needed to obtain information about how the brain works to improve understanding of pathological changes. Additional non-invasive novel technologies, like magnetic resonance spectroscopy (MRS), provide information on the chemical composition of the brain. They represent potentially powerful tools to gather data on brain biochemistry; however, at present the information they can provide is much cruder than that provided by more precise methods, like positron emission tomography(PET),ligandbinding, micro-dialysis and immunochemical techniques.
Improvement of molecular and cell biology has reached a point where genetically modified NHP models of brain diseases are becoming available (Yang et al., 2008). Such genetically modified models will, potentially, be of even higher predictability power for human outcomes than rodent genetically modified models.
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Section3.1.4 Use of NHP in Neuroscience, p.17 -20.
The SCHER opinion states:
3.1.5.Use of NHPs in Xenotransplantation
The shortage of organ donors for transplantation is a major societal problem and the waiting lists continue to grow due to limited organ supplies. Only a minority of patients who may benefit from a transplant will be able to receive one and 10-20% of patients on the waiting list for organ transplants will die before a donor organ becomes available (McManus et al., 1991; Leichtman et al., 2008). Furthermore, as the transplants themselves will also need replacing, this will exacerbate the situation. Novel sources of organs may help to reduce this shortage. In addition to treatment of the terminal failure of organs such as kidney, lung, liver and heart, transplantation is also being seen as a therapy for other diseases such as cystic fibrosis and for patients affected by diabetes and Parkinson disease.
The pig represents the most likely candidate as a source animal and NHPs represent the only useful proof-of-concept species. However, there are serious immunological incompatibilities between pigs and primates based on a specific immune response (anti- αGal), and only OW primates (such as baboons and cynomolgus), great apes and humans have anti-αGal antibodies. While rodents have been generated that exhibit an anti-αGal immune response, the response is weak, severely limiting the credibility of results in experimental models of xenotransplantation (Gock et al., 2000). In addition, there are several concerns over infections transmitted between source animals and humans, physiological functioning, and long term side effects due to the degree of immunosuppression required.
However, some xenotransplants have demonstrated a 2-3 year recipient survival in life- supporting NHP models. This indicates that long-term survival of a xenotransplant is achievable, even when clinically acceptable immunosuppressive regimens are used (Zhong et al., 2003).
Source & ©: SCHER,
Section3.1.5 Use of NHPs in Xenotransplantation, p.20 -21.
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