Neuroscience Biomarkers and Biosignatures Converging Technologies, Emerging Partnerships: Workshop Summary (2008) / Chapter Skim
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4 Neurological and Eye Diseases
4 Neurological and Eye Diseases
Pages 55-70
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From page 55... ...
A rational approach to biomarker development hinges on two key elements: better understanding of the etiology and pathogenesis of a given disorder, and the use of data and stored biological samples from ongoing and prior clinical trials. In Session IV, workshop participants discussed several areas of neurological medicine where a highimpact biomarker could emerge, including Parkinson's disease, multiple sclerosis, stroke, spinal muscular atrophy, and retinal degeneration.
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From page 56... ...
Uric acid levels that are too high are responsible for gout, but higher uric acid levels at the middle ranges found in the Parkinson's clinical trials turned out to reduce the risk for progression of Parkinson's disease by approximately 25 percent, according to a published meta-analysis of observational studies, reported Shoulson (Weisskopf et al., 2007)
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From page 57... ...
He also pointed out that the reanalysis of the clinical trial data was not only supported by the National Institutes of Health, but was also supported by pharmaceutical companies. He expressed the hope that DNA collection from clinical trials might allow whole-genome scanning to search for genotype markers related to biomarkers of risk, disease progression, or response to treatment.
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From page 58... ...
Generalized and regional brain and spinal cord atrophy measurements are currently being evaluated as potential primary outcome measures in exploratory neuroprotective trials. The lack of a good biomarker for the progressive stage of disease motivated Giovannoni's laboratory to begin a decade-long search.
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From page 59... ...
The oncology guidelines begin with the recognition that the guidelines given in the paper cover standardized reporting of materials and methods, including patient selection, specimen characteristics, assay methods, reporting of results, analysis and presentation, and discussion. With the cancer field as its model, Giovannoni and his European colleagues have created a "BioMS Consortium." They plan to issue at least three consensus papers, the first of which covers biobanking (i.e., the FIGURE 4-1 Scientific process for biomarker validation.
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From page 60... ...
The most important yet thorny issue is the incorporation of potentially new biomarkers into clinical trials. These are potential biomarkers that are not accepted outcome measures but that may become useful in the future with further analysis.
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From page 61... ...
Steps for industry • Incorporate potential biomarkers into clinical trials. • Miniaturize and multiplex assays using emerging technologies, par ticularly for use in animal models.
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From page 62... ...
Rarely have trials required an objective confirmation of the presence of biological target for patient selection, and even less frequently have they required evidence of a drug's target biological activity to move a drug from Phase II to Phase III. He characterizes this enormous obstacle to progress as the "disconnect between laboratory successes and larger clinical trials" and argues that it must be tackled head-on by development of better biomarkers.
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From page 63... ...
. Current and previous clinical trial data are still valuable for pooling because new ways to analyze MRI results have been developed and thus can be applied to the raw data.
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From page 64... ...
There is also a need, said Warach, to refine our definition of the ideal "penumbral" patient for clinical trials, as well as to refine definitions for outcome and validation. The pharmaceutical industry has embraced this approach, and there are several ongoing international collaborations, but the effort needs to be greatly expanded to cover greater academic and industry participation, considering that there have been about 20 completed or ongoing acute stroke trials utilizing MRI.
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From page 65... ...
Several drugs are already being tested in investigator-initiated clinical trials supported by NINDS, although some are open-label and thus potentially vulnerable to what has been found in controlled trials: a large placebo effect. While large pharmaceutical companies are thus far noncommittal with respect to SMA, Winberg stated that her organization foresees, with further progress in biomarker development, a sizable market―$500 million to $1 billion in annual revenues -- that may be attractive to biotechnology firms (Box 4-2)
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From page 66... ...
. In one study, SMN mRNA was assayed by quantitative reverse transcription polymerase chain reaction, and SMN protein was assayed by a cell immunoassay.
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From page 67... ...
To facilitate biomarker development, Winberg first recommended a more practical, sensitive method for assaying SMN protein. Current approaches such as quantitative western blotting, cell immunoassay, or ELISA all require significant blood volumes due to the low level of SMN protein expression.
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From page 68... ...
Other markers, some of which have been available for 150 years, screen for disorders of photoreceptors found on retinal ganglion cells. More broadly, Sieving pointed out that the vision field has been remarkably successful for the past 20 years in identifying mutated genes associated with retinal neurodegenerative disorders.
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From page 69... ...
These discoveries are not only of interest to the vision field, but may also have applications elsewhere: some of the complement proteins associated with macular degeneration are similar to those associated with other neurodegenerative disorders. The value of this overlap becomes even more evident with the new imaging technologies developed for retinal imaging.
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From page 70... ...
He ended his presentation with the message that the science is poised to take advantage of ultra-high-resolution imaging tools to develop dynamic functional markers for studying neurodegenerative retinal diseases as well as other neurodegenerative disease. The insights gained can be applied to understanding pathophysiology as well as providing outcome measures for clinical trials.
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