Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter.
Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 21
3
Translation from Animal Models to the Clinic:
Case Examples from Neuroscience Research
The first day of the workshop included concurrent breakout groups
intended to facilitate in-depth analysis of the translational success of an-
imal models in six areas of neuroscience research. Those areas are Alz-
heimer’s disease, neurodegeneration, stroke, addiction, schizophrenia,
and pain. In preparation for the subsequent workshop sessions, breakout
groups focused their discussions on three key questions:
1. Would this research area benefit from a new or improved
standardized animal model?
2. How well do animal model and human clinical endpoints
correlate in this area of research?
3. What is needed to bridge the translational gap between animal
models and clinical science in this area?
These smaller breakout groups enabled discussions about the role and
effectiveness of animal models in the development of therapies for nerv-
ous system disorders. Following the breakout discussions, each group
moderator summarized the main points of discussion for all attendees.
ANIMAL MODELS FOR ALZHEIMER’S DISEASE
In discussing current animal models for Alzheimer’s disease it is im-
portant to think about the human phenotype and what is being modeled in
terms of the animal phenotype. The moderator, Bradley Hyman, profes-
sor of neurology at Harvard Medical School, said that animal models of
21
OCR for page 22
22 ANIMAL MODELS FOR NERVOUS SYSTEM DISORDERS
Alzheimer’s disease, based on the genetics of the disease and the closely
related frontotemporal dementia, replicate at least some of the pathology.
Researchers have been successful at modeling very specific aspects of
Alzheimer’s disease in the mouse (e.g., plaques, tangles). Although these
are incomplete models of the human disease, they have been well re-
ceived in the field as potentially relevant models for use in drug discovery.
Patients with Alzheimer’s disease will display both amyloidopathy
and tauopathy; however, scientists often focus, in a reductionist way, on
one or the other in an animal model. A participant added that even
though the anatomy in the mouse is different than the human, mutant tau
mice are relatively good models in that they recapitulate tau-dependent
neurodegeneration. This has led a number of companies to focus on anti-
bodies that block tau-dependent neurodegeneration in these mouse models.
Hyman reiterated that mouse models are partial, or incomplete, mod-
els of the overall human phenotype. In an animal model, pathological
changes are studied in the context of a unique and isolated event (i.e.,
lesion) over a relatively short period of time. Alzheimer’s disease, as it
occurs in humans, is the sum of how lesions occur and evolve over the
course of many years or decades. Mapping where in the evolution of the
human disease an individual mouse phenotype model fits is an important
and often uncertain piece of information. Hyman questioned the hypothe-
ses tested in humans that do not have exact correlates in animal models
(e.g., differences in when amyloid deposition occurs between animal
models and in human disease).
Several participants also discussed the use of imaging and fluid bi-
omarkers in both animal models and clinical research (e.g., positron
emission tomography or PET); ligands that can identify beta-amyloid
load in the brains of humans; analysis of beta-amyloid tau and phospho-
tau as biomarkers in cerebrospinal fluid. These types of biomarkers are
now used for early diagnosis and to monitor disease progression in hu-
mans and many participants discussed the need to translate them back
into animal models. As new therapeutics are examined, using similar
biomarkers in both animal models and humans may allow for better
translation of animal findings into humans. It was noted that the
Alzheimer’s Disease Neuroimaging Initiative (ADNI) is working toward
Standardization of Alzheimer’s disease biomarkers across the 57 ADNI
sites, enhancing quality assurance, quality control, and better analysis of
the clinical and imaging data in the ADNI public database.
OCR for page 23
CASE EXAMPLES 23
In summary, Hyman emphasized the following about Alzheimer’s
disease animal models:
• Some mouse models exist that are close genocopies of inherited
early-onset disease and have been well received as potentially
relevant models.
• Mouse models are incomplete models of the human phenotype.
• Behavioral results in mouse models are not as robust as biochem-
ical and neuropathological readouts.
• There is a need to better match animal models to the appropriate
stage of human clinical disease.
Animal models are limited in terms of how far they can be extrapolated
toward the human condition. However, compared to many other types of
neurologic diseases, Alzheimer’s disease research has some very promis-
ing successes that can be built upon.
ANIMAL MODELS FOR NEURODEGENERATION
Neurodegeneration research spans Parkinson’s disease, Huntington’s
disease, ammyotrophic lateral sclerosis (ALS), and multiple sclerosis, for
example. Robert Ferrante, professor in the departments of neurological
surgery, neurology, and neurobiology at the University of Pittsburgh,
noted that much of this breakout group’s discussion centered on stand-
ardization of models and whether they accurately reflect neurodegenera-
tive diseases. Ferrante suggested that current animal models for
Huntington’s disease and ALS may accurately reflect not only patho-
physiological mechanisms of human disease, but also neuropathology
and behavioral phenomena. For other disorders, however, it is much
more difficult.
In addition to emphasizing the need for standardization of animal
models of neurodegenerative diseases, participants in this breakout also
discussed enforcing standards for preclinical studies in animals and
raised concerns about the publication of research that cannot be replicat-
ed. It was noted by some participants that although the NIH has set
standards for conducting animal research1 and papers have described
these standards, widespread adoption of these recommendations has been
slow (Kilkenny et al., 2010).
1
See http://www.ninds.nih.gov/funding/transparency_in_reporting_guidance.pdf.
OCR for page 24
24 ANIMAL MODELS FOR NERVOUS SYSTEM DISORDERS
Breakout session participants also discussed reevaluating the scien-
tific approach to drug discovery for neurodegenerative diseases. In gen-
eral, the target-centric approach to neurodegenerative diseases has failed
during the past 50 years and there was discussion of a systems biology
approach to disease research, as well as in silico models of disease.
In discussion whether animal models accurately reflect human neu-
rodegenerative disease, the issue was raised as to whether animal model
studies might be replaced with more Phase 0 clinical trials in humans. In
this regard, there was a call for the identification of pharmacodynamic
markers and biomarkers that are clearly reflective of the disease. For ex-
ample, some noninvasive mechanisms, such as high-definition fiber
tracking in traumatic brain injury and other disorders, reflect what is oc-
curring in the brain and could be developed as a biomarker for many neu-
rodegenerative disorders. Several participants in this group also noted the
need for correlation between the biomarkers used in patients and in ani-
mal models.
Ferrante summarized the main points of discussion in this breakout
session as
• There is a need for more standardization of models reflecting
neurodegenerative disease in patients.
• The scientific approach to neurodegeneration research (e.g.,
target-centric versus systems-based, in silico, etc.) may need to
be updated.
• Research could benefit from increased focus on Phase 0 human
clinical trials.
• There is a need for pharmacodynamic markers and biomarkers
that clearly reflect the disease.
ANIMAL MODELS FOR STROKE
The biology of ischemia is different from that of neurodegeneration,
explained group moderator Constantino Iadecola, professor of neurology
and neuroscience at Weill Cornell Medical College. The stroke process
starts with an arterial occlusion, which can be reproduced effectively in
animals. Several participants noted that animal models of stroke are gen-
erally predictive and adequate. However, the models are not perfect, and
Iadecola said it could be argued that the mechanisms whereby a throm-
bosis or embolus forms in humans may not be mimicked exactly by the
OCR for page 25
CASE EXAMPLES 25
surgical occlusion of an artery in an animal model. Nevertheless, the
basic reaction of the tissue to the occlusion is fairly standard between
different species.
Despite the relative suitability of the animal model for the study of
stroke, clinical trials have not produced effective treatments and many
pharmaceutical companies have scaled back or abandoned stroke re-
search programs. A few participants suggested that failure in the clinic is
partly because endpoints used in preclinical animal studies are different
from those used in clinical trials. For example, animal studies often as-
sess stroke volumes histologically using a chemical marker, which does
not really reflect cell death, while clinical trials measure functional out-
comes. Fortunately, Iadecola said, advanced technologies, such as
diffusion-weighted imaging, can be done in animals and humans, allow-
ing for better correlation between animal and human studies.
One participant noted that there is an ongoing disconnect between
animal studies and clinical trials with regard to what happens in human
stroke and how animal stroke data are obtained. For example, in some
animal studies, the investigational drug is given before the stroke is
induced and protection conferred. However, this is not possible in pa-
tients as drugs are administered 6, 12, or 24 hours after the stroke, with
no effect.
As a result of discussions at a number of symposiums, organizations
have been formed to address this issue. Researchers are working toward
studying stroke in the animal models such that the studies mirror more
closely what happens in the clinic. For example, Iadecola said, research-
ers are using more animals with risk factors for stroke, such as diabetic
animals and aged animals as opposed to the younger “teenage” animals
on which classic stroke work has been based. At the same time, clinical
trials are taking into account the conditions under which protection has
been observed in animal studies (e.g., sex of animals, time window of
drug administration).
In summary, Iadecola highlighted the main points from this breakout
session:
• Although neuroprotection has been demonstrated in numerous
animal studies, treatment of humans has not been effective.
• Adequate animal models of stroke exist, but successful
translation of the science from animal models to humans has
been limited.
OCR for page 26
26 ANIMAL MODELS FOR NERVOUS SYSTEM DISORDERS
• The discordance between animal and human studies may be due
to bias in study design (e.g., different endpoints) or to the failure
of animal models to mimic clinical disease adequately.
ANIMAL MODELS FOR ADDICTION
Athina Markou, professor in the department of psychiatry at the Uni-
versity of California, San Diego, described the development of the smok-
ing cessation drug varenicline as an example of successful development
of a therapy for addiction. Markou speculated, however, that the success
of varenicline in clinical trials is attributable more to the fact that there
was a very strong theoretical rationale and less to the translation of pre-
clinical animal studies. The animal models used were valid models, she
said, but they were simple.
In contrast, despite the significant amount of research that has fo-
cused on dopamine, there are almost no drugs that have made it to the
market for the treatment of addiction. Markou noted that there is disa-
greement as to why this is the case. Some argue that the hypothesis that
dopamine mediates dependence and addiction for all drugs of abuse is
incorrect. A counterpoint is that the clinical trials of dopaminergic drugs
have not been done properly or perhaps have not been done at all. There
are potential targets, such as the dopamine D3 receptor, but Markou
noted there is currently little interest on dopaminergic targets by pharma-
ceutical companies. Other potentially good targets have not been ex-
plored sufficiently and breakout group participants discussed the need to
incentivize industry and to educate pharmaceutical manufacturers that
there is a significant market for addiction treatments.
Unlike some other nervous system disorders (e.g., schizophrenia
where the etiology is not definitively known), the etiology of drug de-
pendence is known to be excessive exposure to the drug. As such, ani-
mals can be similarly exposed to a drug and studied. Several breakout
participants noted that models of addiction exist, although there is always
room for improvement. For example, it was noted that additional empha-
sis is needed on more sophisticated models, such as models that examine
the switch from drug experimentation to addiction or of relapse. A few
participants in this breakout session raised concerns that a standardized
animal model of addiction might not be the best approach. Rather, it was
suggested that studying a variety of models that employ different ap-
proaches could provide converging evidence.
OCR for page 27
CASE EXAMPLES 27
One issue for animal models of addiction is the heterogeneity of the
human population with regard to addiction. The vast majority of people
who experiment with drugs do not become dependent, suggesting a ge-
netic component to addiction. In fact, genetic studies have provided some
potential targets and it was suggested that one way to move forward is to
try to over- or under-express these genes in mouse models and to study
the heterogeneity of addiction development.
Finally, participants in the breakout session discussed concerns with
clinical trials. As in other breakout groups, the need for cross-validation
of animal model endpoints with clinical measures was noted. Also, cur-
rent clinical measures for addiction studies were said to be inadequate in
that the primary outcome measure is drug consumption—did the patient
stop taking the drug or not? There are many processes that lead to addic-
tion or to lack of abstinence that are not assessed in clinical trials,
Markou noted. For example, is drug consumption the result of physical
withdrawal or perhaps due to some cue that reminded the patient of the
drug? For alcohol dependence, is controlled use of alcohol an acceptable
endpoint? Patient compliance is also an issue. In many clinical trials for
addiction, it is not clear whether the patients have actually taken the ther-
apeutic drug and failure of the trial may be because the patients do not
achieve adequate levels of the therapeutic drug in their system.
In summary, Markou highlighted the following points made by vari-
ous participants in this breakout group:
• There are good animal models of addiction. Rather than stand-
ardization of models, many participants noted that the use of
multiple models that employ different approaches could provide
converging evidence.
• Genetic animal models may be helpful in understanding the het-
erogeneity of human addiction.
• The many potential therapeutic targets for addiction that have not
been adequately researched and incentives for research in this
area may be needed.
• Cross validation among animal models, clinical endpoints, and
processes that are assessed in human trials is lacking.
ANIMAL MODELS FOR SCHIZOPHRENIA
In the breakout session on animal models for schizophrenia, much of
the discussion focused on processes, explained breakout moderator Holly
OCR for page 28
28 ANIMAL MODELS FOR NERVOUS SYSTEM DISORDERS
Moore, associate professor of clinical neurobiology in psychiatry at
Columbia University. Topics included the neurobiological processes that
might underlie psychological processes disrupted in schizophrenia; the
process of doing research; and the process of dialogue between clinicians
and researchers using animal models.
Many participants in this breakout session believed that current ani-
mal models for schizophrenia, while informative, are not adequate. It was
noted that there are useful assays of behavior and cognition and of the
neurocircuitry mediating the cognitive process affected in schizophrenia.
However, divergent opinions were expressed on how useful those assays
are and whether it is necessary to assay neurocircuitry or whether looking
for direct impacts of therapeutics on behavior is sufficient. Animal mod-
els are being developed to probe the neurocircuitry underlying cognitive
deficits, as well as the basic processes underlying psychosis and negative
symptoms in schizophrenia.
Moore noted that some breakout group participants thought that the
path forward is to go back to clinical and epidemiological research and
ask “what is wrong” in schizophrenia. One simple approach to answer
this question would be to examine patient behaviors while imaging their
brains. This would allow researchers to determine what is behaviorally
and cognitively aberrant and what neurocircuits are activated in correla-
tion with the observed deficits.
Armed with that information, researchers could develop assays in an-
imals that have homology with assays used in the clinic. First, however,
there needs to be reliable and objective assays for humans that can pre-
dict a clinically significant change such as worsening or improvement in
the patient’s clinical profile. For animal modelers, clinical outcomes such
as reduction in symptoms based on subjective scales are not useful. On
the other hand, an objective assay of cognition and behavior in humans
without data on the clinical significance of these outcomes is also not
helpful.
In some cases, objective assays in humans and the homologous as-
says in animals may be very similar. For example, prepulse inhibition
measurement of sensorimotor gating is similar across animals and hu-
mans and is mediated by the same circuits in the brain. In other cases,
assays that are guided by similar circuits do not look the same in an ani-
mal as they do in a human from a phenomenological point of view.
Moore noted that many breakout session participants thought that
homology at the level of neurocircuits might be a useful starting point for
dialogue between clinicians and researchers that use animal models about
OCR for page 29
CASE EXAMPLES 29
what mediates symptoms or behavioral pathology. Others suggested that
it is not necessary to understand how neurocircuits mediate an aberrant
behavior; that it would be possible to have a reliable and validated assay
of a problematic behavior from a psychological point of view (e.g., an
assay of a sensorimotor deficit). Another concern raised by one partici-
pant was that many animal models of schizophrenia focus on primary
pathology and not how drugs might act on or become a compensatory
mechanism.
Finally, once there are assays in animals that have some homology
with the assays used for humans and which have been shown to predict
clinically significant outcomes or functional outcomes, are those animal
models being fully used? Studying systems in control, or intact, animals
is relevant for target validation and pharmacodynamics. Once studies in
an intact animal establish that the drug is binding to circuits of interest
and modulating both circuit activity and behaviors known to be mediated
by that circuit, the question remains whether the drug will work on that
same circuit and to the same extent in humans. Several group participants
emphasizes that this is where an animal model of disease guided by epi-
demiology and symptomology is important.
Moore summarized the main points of this breakout session as
• Animal models and human clinical research inform each other.
• Control, or intact, model systems are useful for target validation
and pharmacodynamics.
• Animal models of disease would benefit if they were guided by
epidemiology and symptomology.
• There is a need for animal assays that are translatable and predict
clinical outcomes and for assays to have some homology across
species and determinants.
Ideally, once an appropriate animal model is in place, the clinical tri-
als would be designed to ask the same questions that the animal models
asked, using the same objective assays in the clinical trials that were cho-
sen for use in the animal studies because, at the very beginning of the
process, they were objective assays that had some clinical relevance.
OCR for page 30
30 ANIMAL MODELS FOR NERVOUS SYSTEM DISORDERS
ANIMAL MODELS FOR PAIN
A large number of animal models are used by pain researchers. Par-
ticipants in this breakout session discussed the adequacy of these models
and the appropriateness of the assays used relative to clinical outcome
measures.
In some ways, the field of pain research is unique in that it is possible
to mimic the initial inciting events, explained A. Vania Apkarian, profes-
sor in the Neuroscience Institute at Northwestern University and group
moderator. Researchers can cause peripheral neuropathy, for example,
and study diabetic neuropathic pain-related behavior in animals. Classi-
cally, the outcome measure in pain studies has been nociception, on the
assumption that reflexive outcomes (e.g., sensitivity to touch or heat)
correlate to some extent with the human condition.
Apkarian relayed that many group participants felt there were many
useful animal models of pain and that a standardized model was not
needed. Rather, to make the most of existing models, it is important to
ask the right questions. As in other sessions, participants also discussed
the need for biomarkers that can be assayed in humans and animals alike.
Human brain imaging studies are changing the field of pain research
through investigation of chronic pain conditions in humans, Apkarian
said. There was discussion about the need to start looking at correlates of
chronic pain in animal models. As current models are essentially models
of inciting a painful condition, the question has not been asked as to what
is the causal or a critical parameter that induces the maintenance of pain.
Chronic pain is not just nociception. Pain interacts with and reorganizes
the brain. Injuries in humans may or may not lead to chronic pain, sug-
gesting that something genetic in the brain needs to be considered in ad-
dition to the injury. Many participants indicated that much can be learned
from genetic models in mice that might inform research on the human
condition.
In summary, participants in this breakout session raised the following
issues with regard to animal models of pain:
• Many existing animal models of pain might be more useful if re-
searchers ask the right questions.
• Pain is more than just a sensation and appropriate measures are
needed in existing animal models to address this complex issue.
• In particular, several participants were interested in identifying
mechanisms for inciting pain versus maintenance of pain and
OCR for page 31
CASE EXAMPLES 31
understanding the mechanisms of chronic pain in humans.
• The usefulness of mouse genetic models and corresponding ani-
mal and clinical neuroimaging biomarkers was also discussed.
ANIMAL MODELS ADDRESSING
NEURODEVELOPMENT
In the open discussion following the breakout group summaries, a
participant raised another subarea of neuroscience research as an offshoot
of the discussions of models for schizophrenia and addiction—animal
models of what may essentially be developmental disorders.
Moore pointed out that although models of schizophrenia in adult an-
imals are used for pharmacologic studies, knowledge of the epidemiolo-
gy of schizophrenia has led to the development of models where the
perturbation is made quite early in development, when risk factors for the
disease come into play. Although the perturbations are made early in de-
velopment, behavioral and neurological outcomes traditionally have not
been studied until those animals were adults, presumably because that is
when the disease emerges in humans. Only recently are researchers start-
ing to think about looking at different stages in disease development and
potential strategies for prevention.
Moore noted that people who are at high risk for the psychopatholo-
gy associated with schizophrenia are not asymptomatic before they be-
come psychotic. Rather, they have phenotypes that could be identified,
characterized, and targeted for treatment (Kaur and Cadenhead, 2010).
That treatment may delay or prevent psychosis might significantly im-
pact functional outcome even though the person is still undergoing a psy-
chotic episode. Researchers can start looking for signs earlier in people
who have a first degree relative with schizophrenia and can look at pro-
dromal patients who have been clearly identified as at risk using well-
characterized and accepted scales, and ask what treatment is needed prior
to the onset of symptoms.
Moore suggested that there should be less focus on predicting who
may become psychotic and trying to prevent that and focusing more on
treating the pathology affecting them at any particular time in their lives.
There is a real need for a developmental perspective to schizophrenia,
she said, and animal models can help elucidate this.
Many changes in the brain occur during adolescence, but that does
not mean that adolescence is a pathology. Perhaps the parts of the brain
OCR for page 32
32 ANIMAL MODELS FOR NERVOUS SYSTEM DISORDERS
that are changing at the fastest rate during adolescence may be the most
vulnerable. If those areas overlap with the circuits that are implicated in
anxiety, drug abuse, or depression, for example, it may provide clues to
the points of vulnerability in that circuit at that time. These are still basic
research questions.
Markou noted that people who start tobacco smoking in adolescence
have the hardest time quitting. Therefore, it would be important to extend
animal models of addiction to this developmental stage as well.
