Neuroprotection “renaissance” offers hope for improved stroke therapies in future

1907
Johannes Boltze

The “renaissance” of neuro- and cerebroprotective paradigms, coupled with “the advent of new ideas”—such as the concept of ‘transient neuroprotection’ to preserve the penumbra—appears to offer promise in interventional stroke care. This was arguably the prevailing message offered by Johannes Boltze (University of Warwick, Coventry, UK) at the Barts Research and Advanced Interventional Neuroradiology (BRAIN) conference (5–8 December 2022, London, UK) in a presentation on neuroprotective therapies ‘in the recanalisation era’.

Boltze initially opined that recanalisation has been something of a “gamechanger” in the field recently but that, despite this, stroke interventions are still only beneficial to a minority of patients, with key reasons for this being time lost during the prehospital phase; limited access to capable centres; and certain comorbidities.

Drugs and proteins, the speaker continued, are among leading approaches currently being investigated as a means for minimising cerebral infarction and, thus, improving clinical outcomes following an acute ischaemic stroke.

Improving the supply of oxygen to the brain following a stroke is one neuroprotective mechanism that is believed to offer promise, according to Boltze, who highlighted the role H-NOX proteins—high-affinity nitric oxide sensors—can play here. A recombinant variant of these proteins, named Omniox-Ischemic Stroke (OMX-IS, Omniox), has already been investigated extensively in cardiovascular conditions, and is now being studied in acute ischaemic stroke, with recent data from animal models indicating that OMX-IS can “buy a significant amount of time” for the patient, he added.

Boltze elaborated that, overall, these studies have found “no difference” in infarct size when the protein was administered, but that the time gained in the treated animals was more than two hours—which he reiterated constitutes a “significant” saving.

In addition, reducing oxygen consumption, such as via adenosine A1 and A3 receptors, offers another frontier for mitigating against cerebral infarction, according to Boltze. Firstly, he touched on an A1 receptor agonist that has shown promise in mouse models—reducing overall infarct volume, neurological deficit scores and mortality rates—before highlighting positive preclinical findings with AST-004 (Astrocyte) in non-human primates, including total infarct volume reductions that were “on the very edge of statistical significance” and “quite favourable” pharmacokinetic endpoints. The latter has now progressed to a Phase 1 clinical trial, which is ongoing.

“When it comes to the drugs and proteins I [have] introduced to you, we see some promising yet, what I would call, ‘realistic’ results—it is definitely not a golden bullet,” the speaker added. “They may be doing something good on [the surface] but they are not curing stroke as we believed [they could] in the past.”

Boltze further noted that large animal experiments are becoming more important in testing these drugs and proteins, thanks to the “very interesting” parallels they offer versus human stroke patients, and this is reflected in the clinical trials that are now also underway here.

In the second part of his presentation, Boltze discussed the use of cell treatments in neuroprotection, stating: “Clinical trials have been conducted all over the world—mainly using adult cell populations, which are believed to be much safer to employ. And that has indeed [been shown], but the overall outcomes have been rather neutral, and this has made the field a little bit quiet recently.”

He went on to note, however, that this is more pertinent in the Western world than in Asia, and some clinical investigations, such as the MASTERS-2 trial assessing the MultiStem stem cell product (Athersys), are underway.

MultiStem progressed to a full clinical trial after being found to be “safe and well tolerated”, and managing to show “very modest benefits”, in a Phase 2 clinical study. Here, Boltze noted a high level of heterogeneity in the Phase 2 study population, and substantial differences between the chosen therapeutic time window as compared to prior preclinical research. Nevertheless, the trial did see 14.9% more patients achieve the specified endpoints (modified Rankin Scale [mRS] 0–2 and a minimum reduction of 75% in National Institutes of Health Stroke Scale [NIHSS] score from baseline) in the MultiStem treatment group versus a placebo—which Boltze described as “very modest” yet statistically significant and “clinically meaningful”.

The speaker also highlighted another existing problem in this area—the fact that intravenously transplanted cells reach the brain in “very small numbers”, which may detract from the efficacy of such treatments. Administering them arterially, immediately after recanalisation, is an approach that would not have been technically feasible in the past but may mean a greater number of cells end up in the brain, Boltze continued. However, he conceded that intra-arterial administration “may not always be safe” and optimisation of such procedures is likely still required for some cell populations as well.

Boltze concluded by noting that these experimental therapies offer hope within interventional stroke care, and there is a chance they will translate to improved clinical solutions in acute ischaemic stroke further down the line. Furthermore, the ‘recanalisation era’ means these therapeutic agents can be applied “wherever and whenever we need them”, in theory, and transient protection of the penumbra offers a new approach in this space.


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