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New Protein Marker Could Enable Five-Fold Increase in Stroke Patients Eligible for rt-PA Therapy

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University of Geneva researchers in collaboration with the UK's Proteome Sciences have identified a protein marker that could help doctors better determine the time of stroke onset.

This finding, detailed in a paper published last week in PLoS One, could significantly expand the number of ischemic stroke patients eligible for treatment with "clot-busting" recombinant tissue plasminogen activator, or rt-PA, therapy – marketed by Genentech as Activase.

Because rt-PA treatment can cause hemorrhagic conversion – bleeding in the brain – if administered too long after the onset of stroke, current US guidelines require that it be administered within three hours of a stroke occurrence. EU guidelines require that it be administered within four and a half hours.

Such guidelines, University of Geneva researcher and study author Jean-Charles Sanchez told ProteoMonitor, present a challenge due to the fact that many strokes occur when patients are asleep or incapacitate patients so that they are unable to communicate the time of onset. Such patients – which constitute roughly 35 percent of stroke cases – are automatically ruled out for rt-PA treatment.

Currently, said Proteome Sciences' chief operational officer Ian Pike, stroke patients undergo imaging to determine whether they are suffering from an ischemic or hemorrhagic stroke. This imaging also determines if they are within the time range for safe rt-PA treatment.

However, patients unable to remember or communicate their stroke onset time are often not prioritized for this imaging, meaning many miss the opportunity to receive rt-PA treatment even though they might have arrived at the hospital in time. A protein biomarker test capable of identifying patients within the required time window could be used to prioritize patients for immediate imaging – leading to more patients eligible for rt-PA.

To identify the marker, the researchers performed an analysis of 29 plasma proteins linked to stroke-related brain damage, measuring them in two separate cohorts – one comprising 103 cases and 132 controls collected at Geneva University Hospital and a second comprising 155 stroke patients admitted to Barcelona's Vall d'Hebron Hospital.

Via this analysis, they identified glutathione S-transferase-π, GSTP, as potentially useful for determining stroke onset time, determining that the protein could distinguish between early – within the three-hour window – and late – outside the three-hour window – stroke patients with a specificity of 91 percent and a sensitivity of 50 percent.

According to Pike, this data indicates the marker could potentially increase the number of stroke patients eligible for rt-PA therapy by five-fold.

The marker could also prove useful for alternative stroke treatments that also must be done within a given time window, such as removing clots via balloon catheters, he told ProteoMonitor, noting that he expects the marker to "realistically transform how we look at and manage stroke patients."

MingMing Ning, a stroke neurologist at Massachusetts General Hospital and director of the Clinical Proteomics Research Center there, who was not involved in the study, agreed that the marker could be significant, noting that determining onset time "is one of the most important questions in stroke."

Less than 10 percent of all ischemic stroke patients currently receive rt-PA therapy, she said. "So major effort has been devoted to 'timing' stroke by biomarkers, imaging, et cetera."

Ning is herself involved in stroke protein biomarker work, including through a collaboration with Thermo Fisher Scientific's BRIMS Center director Mary Lopez and MGH Neuroprotection Research Laboratory director Eng Lo (PM 2/25/2011).

She noted that groups aside from those involved in the PLoS One paper have also been looking for onset time biomarkers, with a number focusing on panels measuring protease activity.

The GSTP work "is a great start," Ning told ProteoMonitor, adding that now further confirmation in additional multicenter cohorts was needed.

"It would also be good to look at other confounders that may influence GSTP levels," she said. "Most importantly, to find the mechanism of why this particular marker is involved in early stroke. Is it specific to the brain or other acute events?"

According to Pike, much of this additional validation work will be driven by diagnostics firm Randox Laboratories, to which Proteome Sciences has sold a non-exclusive license to several stroke-related protein biomarkers, including GSTP.

"Going forward, it's clear that there will be a need to generate supporting data that can be submitted to regulatory authorities in Europe for CE marking and ultimately for looking at US regulatory approval," he said. "The time scale for that will be dependent on Randox and how they ramp up their manufacturing process and final development strategy."

Proteome Sciences signed the stroke marker licensing agreement with Randox in April. The agreement provides Proteome Sciences with seven-figure US dollar license and development milestones as well as double-digit percentage royalties on sales, and includes, in addition to GSTP, a panel of five protein markers for rapid diagnosis of stroke.

Pike suggested that GSTP could also prove useful in clinical studies for new stroke treatments.

The marker's "alignment is not only with [rt-PA], but also with experimental medicines coming and with physical interventions [such as] with catheters," he said. "I think the initial uptake of this test is going to be in support of trials for new thrombolytic agents, many of which have a slightly wider therapeutic window because they have slightly different modes of action."

He added that Proteome Sciences and the University of Geneva team are also looking "at how useful this marker can be in monitoring patients [receiving various treatments] for indicators of hemorrhagic transformation prior to the appearance of clinical symptoms. And, again, with that tool in hand it may be possible to extend the window for these clot-digesting treatments a little wider than the current window."

Sanchez noted that his team is also involved in work looking at GSTP as a prognostic marker for evaluating the severity of stroke and a patient's potential outcome.

"This is a completely different intended use," he noted. "It is to try to predict very early which patients will recover quickly and be able to leave intensive care and which [patients] will need longer in intensive care. That is another study ongoing where GSTP seems to be very interesting."

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