When should non human primates be used as animal models?

Transcription

1 When should non human primates be used as animal models? Roger Lemon Sobell Department of Motor Neuroscience and Movement Disorders UCL Institute of Neurology Queen Square Animal Research Regulation Meeting July 2011

2 Total of Old World monkeys used in 2010: 3585 (0.1% of all animal research procedures) Purpose: Applied (toxicology etc): 2894 (81%) Fundamental research: 270 (6%)

3 EU Directive 2010/63/EU Recital 17 Having regard to the present state of scientific knowledge, the use of non human primates in scientific procedures is still necessary in biomedical research. Due to their genetic proximity to human beings and to their highly developed social skills, the use of non human primates in scientific procedures raises specific ethical and practical problems in terms of meeting their behavioural, environmental and social needs in a laboratory environment. Furthermore, the use of non human primates is of the greatest concern to the public. Therefore the use of non human primates should be permitted only in those biomedical areas essential for the benefit of human beings, for which no other alternative replacement methods are yet available.

4 EU Directive 2010/63/EU Recital 13 The methods selected.. and require the use of species with the lowest capacity to experience pain, suffering, distress or lasting harm that are optimal for extrapolation into target species. Both recitals urge that NHPs be used only when there is likely to be benefit for humans. Importantly Articles 5 and 8 of the Directive stress that NHPs can be used for basic Research, which of course is important because most of the benefit comes ultimately from key discoveries in fundamental science Examples: Deep Brain Stimulation for Parkinson s Disease Constraint Induced Therapy for chronic stroke patients Brain Machine Interface for paralysed patients

5 Further example: much of the basic research work in the UK on NHPs involves understanding the role of the prefrontal cortex, and this work will inform progress towards treatment of neurological and psychiatric disorders of the frontal lobe: the prefrontal cortex contributes to a multitude of cognitive processes, such as attention, working memory, goal selection, outcome prediction, response inhibition and so forth. They also encompass the knowledge underlying our social behavior, including speech Wise, 2009

6 NHP neuroscience: is it justified? UK Weatherall Report 2006 In the fields of research considered in this study, namely communicable disease, neuroscience and reproductive biology, there is a strong scientific case for maintaining the use of non human primates in some aspects of this work, at least for the immediate future

7 NHP neuroscience: is it justified? UK Weatherall Report 2006 EU SCHER Report 2009 In the fields of research considered in this study, namely communicable disease, neuroscience and reproductive biology, there is a strong scientific case for maintaining the use of non human primates in some aspects of this work, at least for the immediate future

8 NHP neuroscience: is it justified? UK Weatherall Report 2006 EU SCHER Report 2009.Bateson Report 2011 to be published on Wednesday 27 th July 2011 In the fields of research considered in this study, namely communicable disease, neuroscience and reproductive biology, there is a strong scientific case for maintaining the use of non human primates in some aspects of this work, at least for the immediate future

9 In 2004 this report from the Academy of Medical Sciences highlighted the need to promote translation of basic science into clinical practice to improve neurorehabilititation, including better therapies for rehabilitation of hand function

10 Why are hands so important? Stroke: 100,000 new cases per year, 50% have hand disabilities (UK) Spinal injury: 800 new cases per year (UK) Cerebral Palsy: 1800 new cases per year (UK) The loss of hand function is devastating. In a survey of quadriplegic patients, the regaining of arm and hand function was ranked as most important, above bowel and bladder control, sexual function, and standing/walking (Anderson, 2004).

11 Nature Medicine 2008 We discuss crucial differences in the organization of the motor systems and behaviors among rodents, nonhuman primates and humans, and argue that studies in nonhuman primates are critical for the translation of some potential interventions to treat SCI in humans.

12 COMPARATIVE BIOLOGY OF CORTICOSPINAL TRACT There are significant species differences in the organisation of the corticospinal system: size and number of fibres trajectory (dorsal columns/lateral columns) spinal extent (cervical, thoracic, lumbo sacral) pattern of spinal termination (dorsal horn, intermediate zone, motoneuron pools) in primates, the extent of corticomotoneuronal connections is correlated with dexterity, including use of tools Kuypers 1981

13 Increased influence of cortico motoneuronal projection in primates vs non primates Lemon, Ann Rev Neurosci 2008

14 Example: Anti NOGO as a potential treatment for Spinal Cord Injury (1990) First discovered by Martin Schwab in late 1980 s Extensive research in vitro an then in vivo experiments in rats and mice Over 50 papers published This work characterised the active properties of the NOGO (NO GrOwth) protein and demonstrated its mechanism of action. It also developed a means of neutralising it with an antibody (anti NOGO)

15 Example: Anti NOGO as a potential treatment for Spinal Cord Injury Then, the first publications on tests of anti NOGO in macaque monkeys Five further papers on monkeys since. The macaque study was a necessary precursor to the clinical trial, which began in 2006

16 Example: Anti NOGO as a potential treatment for Spinal Cord Injury Phase I (> 50 patients) completed, Phase II started 2010

17 Some key points for research involving NHPs in the UK 1. Continued need for NHP research, especially for neurodegenerative disease and psychiatric disorders.

18 Some key points for research involving NHPs in the UK 1. Continued need for NHP research, especially for neurodegenerative disease and psychiatric disorders. 2. Studies will be complementary to so called alternative approaches (in vitro, in silico, human brain imaging etc). Numbers of animals low, but amount of data obtained is high.

19 Some key points for research involving NHPs in the UK 1. Continued need for NHP research, especially for neurodegenerative disease and psychiatric disorders. 2. Studies will be complementary to so called alternative approaches (in vitro, in silico, human brain imaging etc). Numbers of animals low, but amount of data obtained is high. 3. Note that almost all NHP researchers use these complementary approaches.

20 Some key points for research involving NHPs in the UK 1. Continued need for NHP research, especially for neurodegenerative disease and psychiatric disorders. 2. Studies will be complementary to so called alternative approaches (in vitro, in silico, human brain imaging etc). Numbers of animals low, but amount of data obtained is high. 3. Note that almost all NHP researchers use these complementary approaches. 4. Positive culture of NHP care, role of UK National Centre for 3Rs new Academy of Medical Sciences Report on Animals Containing Human Material an exciting report which proposes an ethical and regulatory framework for this important kind of research, some of which will involve NHPs Let us see some of this research done in the UK!

21 Some threats for research involving NHPs in the UK COST Purchase cost per purpose bred Rhesus macaque ~ 20k (ex VAT) Daily cost of housing/caring per macaque ~ NHP research is expensive: security, welfare standards High cost of NHP research: no trivial or unnecessary work Much greater: high costs will threaten serious NHP research Without some additional investment in infrastructure, how can it compete with other types of research?

22 Some threats for research involving NHPs in the UK COST Purchase cost per purpose bred Rhesus macaque ~ 20k (ex VAT) Daily cost of housing/caring per macaque ~ NHP research is expensive: security, welfare standards High cost of NHP research: no trivial or unnecessary work Much greater: high costs will threaten serious NHP research Without some additional investment in infrastructure, how can it compete with other types of research? REGULATION & BUREAUCRACY Over regulation without real animal welfare benefits must be avoided Another threat could come from moves towards reclassifying Moderate procedures involved in long term neuroscience procedures as Severe

23 Some threats for research involving NHPs in the UK COST Purchase cost per purpose bred Rhesus macaque ~ 20k (ex VAT) Daily cost of housing/caring per macaque ~ NHP research is expensive: security, welfare standards High cost of NHP research: no trivial or unnecessary work Much greater: high costs will threaten serious NHP research Without some additional investment in infrastructure, how can it compete with other types of research? REGULATION & BUREAUCRACY Over regulation without real animal welfare benefits must be avoided Another threat could come from moves towards reclassifying Moderate procedures involved in long term neuroscience procedures as Severe TRAINING Perceived difficulty of doing NHP research may affect our ability to attract the very best young scientists, competitive future?

24 Acknowledgements

25

26 FENS JNS SfN Joint Animals Statement Our Stance The Federation of European Neuroscience Societies (FENS), the Japan Neuroscience Society (JNS) and the Society for Neuroscience (SfN) strongly advocate the responsible use of animals in biological and biomedical research. Animal models are vital and irreplaceable for scientific progress and in combating the devastation of human neurological and psychiatric diseases, which affect more than 1 billion people worldwide, and for improving veterinary health. Animal models must be used appropriately and within humane guidelines, carrying out research that maximizes scientific gain with the least amount of animal suffering. As scientists pursue these advances, we strive to replace and reduce the number of animals wherever scientifically justifiable, and continuously refine experimental procedures to improve animal welfare.

27 Aims and objectives What is needed in our work? The situation we strive for Monkey is well, healthy, well motivated (NB reward related studies) Performs enough trials per session to make statistically worthwhile Puts on weight (but not becoming obese ) Shows normal home cage behaviour Generally: co operates with the experimenter in a positive way, comes out for the experiment, accepts restraint etc etc. Good science is compatible with good welfare (Both monkey and scientist are contented)

28 Definitions: Severe in Annex VIII, EU Directive Severe Procedures on animals as a result of which the animals are likely to experience severe pain, suffering or distress, or long lasting moderate pain, suffering or distress as well as procedures, that are likely to cause severe impairment of the well being or general condition of the animals shall be classified as severe. DO NEUROSCIENCE RECORDING PROTOCOLS FIT WITH THESE?

29 Evidence based review What sort of evidence might be relevant to deciding whether NHPs experience cumulative severity? 1. Weight changes: do monkeys fail to flourish and gain weight? 2. Changes in task performance: does performance decline or deteriorate? 3. Home cage behaviour: do monkeys on procedure behave differently from those who are not? 4. Physiology: are there significant changes in blood biochemistry, renal histology?

30 2. Task related performance 1) In most studies, subjects perform at high cognitive level after >3 years of neurophysiological recording. Still motivated and can be trained to perform new, sometimes more demanding tasks 2) Willingly go out of home cage and voluntarily participate in tasks. Animals choose when and how much to work. 3) In some cases animals will work for fluid reward (with head restraint) even when ad lib water available before testing. Animals find the tasks enriching, do not exhibit signs of distress, and remain highly motivated to work No downside to making experiments as enjoyable as possible for the animal