- Email: [email protected]
Structural MRI biomarker qualification
S810
Featured Research Session F5-03: Qualification of Biomarkers and Disease Models for Improved Treatment Development in Alzheimer’s Disease
aggregation-prone Tau. It should be possible to prevent toxicity by mechanisms or compounds that interfere with aggregation. (2) Tau-induced toxicity can be reversed by switching off the toxic agent or by neutralizing it.
F5-02-06
TAU REDUCTION AS A POTENTIAL TREATMENT FOR ALZHEIMER’S DISEASE, EPILEPSY AND RELATED DISORDERS
Lennart Mucke, Gladstone Institute of Neurological Disease and University of California, San Francisco, San Francisco, Calif, United States. Background: Reducing tau expression from early developmental stages makes mice more resistant to pharmacological induction of epileptic seizures and prevents Abeta-induced neuronal, synaptic and cognitive deficits in human amyloid precursor protein (hAPP) transgenic mice. Even hemizygous knockout mice with 50% tau reduction are well protected compared with tau wildtype controls. To further evaluate the therapeutic potential of tau reduction, we wondered if this strategy was also efficacious and safe when initiated in adults. We also wanted to find out more about the molecules that regulate tau levels in neuronal cells and the mechanisms by which tau reduction is protective. Methods: We placed anti-tau shRNAs under control of a tetracycline-regulatable promoter system, microinjected the transgenes into fertilized oocytes, and crossed the resulting founder lines with transgenic lines expressing the corresponding transactivator in specific neuronal populations. In an alternative approach, we inserted anti-tau shRNAs into viral vectors for stereotactic injection into different brain regions. Mice are analyzed by a variety of biochemical, immunohistochemical, electrophysiological, and behavioral methods. To identify tau regulators, we expressed different indicator genes in neuronal cell lines and are now using these cells to screen a comprehensive RNAi library. Results: We have established several lines of doubly transgenic mice with regulatable neuronal expression of anti-tau shRNA. Preventing shRNA expression by doxycycline treatment from conception resulted in normal cerebral tau levels in adult transgenic mice. Stopping doxycycline treatment in adult mice induced shRNA expression and reduced tau levels by at least 50% in mice hemizygous for the anti-tau transgene. Greater degrees of tau reduction are expected in homozygous transgenic mice. Initiation of tau reduction in adult mice did not cause obvious neurological phenotypes. Detailed analyses of these new models and of mice injected with viral vectors are in progress. Conclusions: Regulatable transgene constructs encoding anti-tau shRNA allow for suppression of neuronal tau in adult mice to levels that were neuroprotective in conventional tau knockout mice. Preliminary observations suggest that tau reduction may be well tolerated also when initiated in adulthood. However, additional work is clearly necessary to fully assess the safety and therapeutic potential of this intervention.
THURSDAY, JULY 21, 2011 FEATURED RESEARCH SESSION F5-03 QUALIFICATION OF BIOMARKERS AND DISEASE MODELS FOR IMPROVED TREATMENT DEVELOPMENT IN ALZHEIMER’S DISEASE F5-03-01
ALZHEIMER’S-SPECIFIC DATA STANDARDS
ations, and CDISC met regularly to determine AD standards which were put out for public comment in Dec 2010. Results: An implementation guide comprises version 1.0 of the AD Therapeutic Area Supplement to the CDISC Study Data Tabulation Model Implementation Guide for Human Clinical Trials (SDTMIG: AD v1.0 AD). Conclusions: Comments from the wider AD community have been included and now published, so health agencies, regulatory authorities and scientists have a better understanding from one clinical dataset to the other. The C-Path website had a large number of AD trials transposed to CDISC format.
F5-03-02
CSF BIOMARKER QUALIFICATION
Holly Soares, Bristol Myers Squibb Company, Wallingford, Conn. United States. Background: Qualification of patient selection and disease progression models are key enablers for clinical trial studies in AD. As a result, the critical path/coalition against major disease (CAMD) has initiated qualification efforts for early disease selection biomarkers and models for disease progression. CSF proteins especially amyloid may provide one of the earliest marker signals. Methods: The goal of the CAMD Alzheimer’s Disease Biomarkers Workgroup is to deliver a research plan to the FDA and EMA that supports successful qualification of patient selection biomarkers and disease progression models. Results: The biomarker focuses upon qualification of CSF ABeta42, total tau and MRI based temporal lob atrophy as tools to enrich identifying an episodically memory impaired, non-demented population at risk of progressing to dementia. Key to the success of both proposals is the importance of data standardization. Conclusions: Qualification guidelines from health agencies have provided a vehicle to better understand the suitability of emerging biomarker tools
F5-03-03
STRUCTURAL MRI BIOMARKER QUALIFICATION
Clifford Jack, Mayo Clinic, Rochester, Minn. United States. Background: A large imaging and pathology literature provides evidence that loss of hippocampal volume is significant in AD. Numerous studies have shown the association of hippocampal atrophy with neurodegenerative pathology at autopsy, with clinical diagnoses of AD or MCI, and with the severity of cognitive disorders and episodic memory deficits due to AD pathophysiology. Methods: Data was obtained from MRI longitudinal follow up in 21 studies, where 18 reported a statistically significant association between baseline hippocampal volume and conversion from MCI to AD, either in the form of hazard ratios or odds ratios, or in a comparison of baseline hippocampal volume between AD converters and stable patients. Results: There is overwhelming evidence to support specific usefulness of this biomarker in patient selection for AD clinical trials. Conclusions: In patients with episodic memory deficit, MRI-derived volumetric measure of hippocampal atrophy constitutes a positive biomarker signature predictive of evolution to AD-dementia type, and thus is useful for enrichment of clinical trial populations entry F5-03-04
APPLICATION/QUALIFICATION OF DISEASE MODELS FOR IMPROVED TREATMENT DEVELOPMENT IN ALZHEIMER’S DISEASE
Marc Cantillon, CAMD Critcal Path Institute, Tuscon, Ariz. United States.
Brian Corrigan, Pfizer, Groton, Conn. United States.
Background: Clinical trials have used many different data conventions which have limited the cross trial power. Global regulatory authorities and scientists cannot compare patient level outcomes including ADAS. Clinical Data Interchange Standards Consortium (CDISC) has become the standard for all regulatory submissions, but specific disease area standards have not been completed. The purpose of this project is to develop AD clinical content data standards for clinical trials data in collaboration between the CDISC and the Coalition Against Major Diseases (CAMD), a program of the Critical Path Institute. Methods: Scientists from the AD clinical community, industry, government agencies, academia, patient advocacy associ-
Background: The need for more quantitative disease, drug, and trial models that can be used across the scientific community has been described by the Food and Drug Administration (FDA), in the Critical Path Initiative, with a goal of developing standardized data, analyses, and models. Methods: Assumptions about disease progression and the time-variant effects of placebo and existing drug treatments for AD form the basis for various decisions made in AD drug development, including decisions relating to trial design and analysis. Results: Developing 1) a longitudinal model for cognition, 2) a simulation tool for use in trials in mild to moderate AD patients, and
Featured Research Session F5-03: Qualification of Biomarkers and Disease Models for Improved Treatment Development in Alzheimer’s Disease
aggregation-prone Tau. It should be possible to prevent toxicity by mechanisms or compounds that interfere with aggregation. (2) Tau-induced toxicity can be reversed by switching off the toxic agent or by neutralizing it.
F5-02-06
TAU REDUCTION AS A POTENTIAL TREATMENT FOR ALZHEIMER’S DISEASE, EPILEPSY AND RELATED DISORDERS
Lennart Mucke, Gladstone Institute of Neurological Disease and University of California, San Francisco, San Francisco, Calif, United States. Background: Reducing tau expression from early developmental stages makes mice more resistant to pharmacological induction of epileptic seizures and prevents Abeta-induced neuronal, synaptic and cognitive deficits in human amyloid precursor protein (hAPP) transgenic mice. Even hemizygous knockout mice with 50% tau reduction are well protected compared with tau wildtype controls. To further evaluate the therapeutic potential of tau reduction, we wondered if this strategy was also efficacious and safe when initiated in adults. We also wanted to find out more about the molecules that regulate tau levels in neuronal cells and the mechanisms by which tau reduction is protective. Methods: We placed anti-tau shRNAs under control of a tetracycline-regulatable promoter system, microinjected the transgenes into fertilized oocytes, and crossed the resulting founder lines with transgenic lines expressing the corresponding transactivator in specific neuronal populations. In an alternative approach, we inserted anti-tau shRNAs into viral vectors for stereotactic injection into different brain regions. Mice are analyzed by a variety of biochemical, immunohistochemical, electrophysiological, and behavioral methods. To identify tau regulators, we expressed different indicator genes in neuronal cell lines and are now using these cells to screen a comprehensive RNAi library. Results: We have established several lines of doubly transgenic mice with regulatable neuronal expression of anti-tau shRNA. Preventing shRNA expression by doxycycline treatment from conception resulted in normal cerebral tau levels in adult transgenic mice. Stopping doxycycline treatment in adult mice induced shRNA expression and reduced tau levels by at least 50% in mice hemizygous for the anti-tau transgene. Greater degrees of tau reduction are expected in homozygous transgenic mice. Initiation of tau reduction in adult mice did not cause obvious neurological phenotypes. Detailed analyses of these new models and of mice injected with viral vectors are in progress. Conclusions: Regulatable transgene constructs encoding anti-tau shRNA allow for suppression of neuronal tau in adult mice to levels that were neuroprotective in conventional tau knockout mice. Preliminary observations suggest that tau reduction may be well tolerated also when initiated in adulthood. However, additional work is clearly necessary to fully assess the safety and therapeutic potential of this intervention.
THURSDAY, JULY 21, 2011 FEATURED RESEARCH SESSION F5-03 QUALIFICATION OF BIOMARKERS AND DISEASE MODELS FOR IMPROVED TREATMENT DEVELOPMENT IN ALZHEIMER’S DISEASE F5-03-01
ALZHEIMER’S-SPECIFIC DATA STANDARDS
ations, and CDISC met regularly to determine AD standards which were put out for public comment in Dec 2010. Results: An implementation guide comprises version 1.0 of the AD Therapeutic Area Supplement to the CDISC Study Data Tabulation Model Implementation Guide for Human Clinical Trials (SDTMIG: AD v1.0 AD). Conclusions: Comments from the wider AD community have been included and now published, so health agencies, regulatory authorities and scientists have a better understanding from one clinical dataset to the other. The C-Path website had a large number of AD trials transposed to CDISC format.
F5-03-02
CSF BIOMARKER QUALIFICATION
Holly Soares, Bristol Myers Squibb Company, Wallingford, Conn. United States. Background: Qualification of patient selection and disease progression models are key enablers for clinical trial studies in AD. As a result, the critical path/coalition against major disease (CAMD) has initiated qualification efforts for early disease selection biomarkers and models for disease progression. CSF proteins especially amyloid may provide one of the earliest marker signals. Methods: The goal of the CAMD Alzheimer’s Disease Biomarkers Workgroup is to deliver a research plan to the FDA and EMA that supports successful qualification of patient selection biomarkers and disease progression models. Results: The biomarker focuses upon qualification of CSF ABeta42, total tau and MRI based temporal lob atrophy as tools to enrich identifying an episodically memory impaired, non-demented population at risk of progressing to dementia. Key to the success of both proposals is the importance of data standardization. Conclusions: Qualification guidelines from health agencies have provided a vehicle to better understand the suitability of emerging biomarker tools
F5-03-03
STRUCTURAL MRI BIOMARKER QUALIFICATION
Clifford Jack, Mayo Clinic, Rochester, Minn. United States. Background: A large imaging and pathology literature provides evidence that loss of hippocampal volume is significant in AD. Numerous studies have shown the association of hippocampal atrophy with neurodegenerative pathology at autopsy, with clinical diagnoses of AD or MCI, and with the severity of cognitive disorders and episodic memory deficits due to AD pathophysiology. Methods: Data was obtained from MRI longitudinal follow up in 21 studies, where 18 reported a statistically significant association between baseline hippocampal volume and conversion from MCI to AD, either in the form of hazard ratios or odds ratios, or in a comparison of baseline hippocampal volume between AD converters and stable patients. Results: There is overwhelming evidence to support specific usefulness of this biomarker in patient selection for AD clinical trials. Conclusions: In patients with episodic memory deficit, MRI-derived volumetric measure of hippocampal atrophy constitutes a positive biomarker signature predictive of evolution to AD-dementia type, and thus is useful for enrichment of clinical trial populations entry F5-03-04
APPLICATION/QUALIFICATION OF DISEASE MODELS FOR IMPROVED TREATMENT DEVELOPMENT IN ALZHEIMER’S DISEASE
Marc Cantillon, CAMD Critcal Path Institute, Tuscon, Ariz. United States.
Brian Corrigan, Pfizer, Groton, Conn. United States.
Background: Clinical trials have used many different data conventions which have limited the cross trial power. Global regulatory authorities and scientists cannot compare patient level outcomes including ADAS. Clinical Data Interchange Standards Consortium (CDISC) has become the standard for all regulatory submissions, but specific disease area standards have not been completed. The purpose of this project is to develop AD clinical content data standards for clinical trials data in collaboration between the CDISC and the Coalition Against Major Diseases (CAMD), a program of the Critical Path Institute. Methods: Scientists from the AD clinical community, industry, government agencies, academia, patient advocacy associ-
Background: The need for more quantitative disease, drug, and trial models that can be used across the scientific community has been described by the Food and Drug Administration (FDA), in the Critical Path Initiative, with a goal of developing standardized data, analyses, and models. Methods: Assumptions about disease progression and the time-variant effects of placebo and existing drug treatments for AD form the basis for various decisions made in AD drug development, including decisions relating to trial design and analysis. Results: Developing 1) a longitudinal model for cognition, 2) a simulation tool for use in trials in mild to moderate AD patients, and