The Spinal Muscular Atrophy Foundation said this week that it has developed a 27- protein plasma biomarker panel for use in SMA research.
The foundation developed the panel in collaboration with Myriad RBM, using the company's DiscoveryMAP protein biomarker discovery platform. According to Dione Kobayashi, a director at SMA Foundation, the panel could prove "a powerful tool to help track progression of SMA and possibly provide a sensitive and objective signal for changes in SMA … due to drug treatment."
SMA is a motor neuron disease that causes spinal cord nerve cell loss, leading to muscular weakness and atrophy. Depending on the severity of the case, the disease can result in the loss of the ability to walk, stand, and breathe, and is the leading genetic cause of death for infants and toddlers. Annually, between 6,000 and 10,000 children are born with the disease.
The SMA Foundation panel emerged from the organization's Biomarkers for SMA study, a 100-plus-patient prospective study that it conducted at 18 sites across North America. BG Medicine performed the initial discovery work for the study, profiling more than 700 plasma proteins via LC-MS. SMA Foundation then moved to Myriad RBM's immunoassay-based DiscoveryMAP platform – which uses a Luminex bead-based system to measure levels of more than 250 proteins in a sample – to verify and validate stages of the process.
"DiscoveryMAP was a great complement to the initial identification work we had done [with BG Medicine]," Kobayashi told ProteoMonitor in an e-mail this week. "It had the great benefit of being filled with analytes that are already being researched and validated as biomarkers for other diseases."
In addition, Kobayashi noted, DiscoveryMAP offered an "expanded ability to identify low-abundance biomarkers" given the higher sensitive of immunoassays compared to typical LC-MS workflows.
Throughput was another consideration, Sam LaBrie, vice president of corporate development at Myriad RBM, told ProteoMonitor, noting that, despite advances in mass spec workflows, running the hundreds of samples required for clinical work remains a challenge.
Mass spec "doesn't have the throughput [needed] for a clinical study," he said. "You can't run hundreds of samples in a reasonable amount of time. So discoveries in mass spec generally need to be translated over to another platform, and [SMA Foundation] had reached the point at which they needed to do that."
A number of the markers identified via the mass spec analysis were also components of the DiscoveryMAP platform, LaBrie said. "So we decided to do a DiscoveryMAP-based project and then their earlier mass spec data and the DiscoveryMAP data was all analyzed together as we made choices about what markers to include."
As it currently stands, the panel is for research purposes only, Kobayashi said, and is not intended for diagnosis of the disease, which is typically done "by genetic testing for deletions or mutations in the [survival motor neuron] genes after clinical presentation of weakness that leads to the suspicion of neuromuscular disorder."
She suggested that the biomarker panel could prove useful in developing a better understanding of the natural history and progression of the disease, particularly as these change in response to improved clinical care.
It could also play a role in drug development, for example "as an additional objective tool to determine if a patient is declining in their motor function or in a clinical trial to determine if their analyte signature is moving toward a milder form of the disease," Kobayashi said. She added that such objective measures are particularly important given that the majority of patients with SMA are children, "and assessment of their status with motor outcome measures requires motivation and cooperation on their part."
Some subsets of the panel might also prove useful for measuring pharmacodynamic changes during drug development, Kobayashi said, although she noted that this would depend on further research into their relationship to SMN protein, which is the target of most therapies currently in development for SMA.
According to SMA Foundation's website, at least 11 pharma companies or research institutions – including Roche, Novartis, Genzyme, and the National Institute of Neurological Disorders and Stroke – have SMA therapies under development. The NINDS is also sponsoring an SMA biomarker study run through its NeuroNEXT research consortium.
What SMA Foundation is "hoping to do is link expression levels of these 27 proteins with disease severity and progression" so as to "allow the drug companies that are performing those trials to use the protein markers as surrogates for those parameters – symptoms and progression," LaBrie said.
He said that Myriad RBM will work on marketing and selling the panel with SMA Foundation, but noted that the latter is "certainly in the driver's seat" and described the two parties' relationship as fee-for-service.
SMA Foundation owns all intellectual property for both the initial protein markers identified via mass spec by BG Medicine and the markers identified and validated on the DiscoveryMAP platform.
The foundation and Myriad RBM continue to collaborate to test the panel, Kobayashi said, adding that the foundation "is actively involved in additional validation studies" for the panel.
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