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Perlecan domain V therapy for stroke: a beacon of hope?

ABSTRACT: The sad reality is that in the year 2012, people are still dying or suffering from the extreme morbidity of ischemic stroke. This tragedy is only compounded by the graveyard full of once promising new therapies. While it is indeed true that the overall mortality from stroke has declined in the United States, perhaps due to increased awareness of stroke symptoms by both the lay public and physicians, it is clear that better therapies are needed. In this regard, progress has been tremendously slowed by the simple fact that experimental models of stroke and the animals that they typically employ, rats and mice, do not adequately represent human stroke. Furthermore, the neuroprotective therapeutic approach, in which potential treatments are administered with the hope of preventing the spread of dying neurons that accompanies a stroke, typically fail for a number of reasons such as there is simply more brain matter to protect in a human than there is in a rodent! For this reason, there has been somewhat of a shift in stroke research away from neuroprotection and toward a neurorepair approach. This too may be problematic in that agents that might foster brain repair could be acutely deleterious or neurotoxic and vice versa, making the timing of treatment administration after stroke critical. Therefore, in our efforts to discover a new stroke therapy, we decided to focus on identifying brain repair elements that were (1) endogenously and actively generated in response to stroke in both human and experimental animal brains, (2) present acutely and chronically after ischemic stroke, suggesting that they could have a role in acute neuroprotection and chronic neurorepair, and (3) able to be administered peripherally and reach the site of stroke brain injury. In this review, I will discuss the evidence that suggests that perlecan domain V may be just that substance, a potential beacon of hope for stroke patients.

SUBMITTER: Bix GJ

PROVIDER: S-EPMC3605814 | biostudies-other | 2013 Mar

REPOSITORIES: biostudies-other

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Project description:Many growth factors, such as bone morphogenetic protein (BMP)-2, have been shown to interact with polymers of sulfated disacharrides known as heparan sulfate (HS) glycosaminoglycans (GAGs), which are found on matrix and cell-surface proteoglycans throughout the body. HS GAGs, and some more highly sulfated forms of chondroitin sulfate (CS), regulate cell function by serving as co-factors, or co-receptors, in GF interactions with their receptors, and HS or CS GAGs have been shown to be necessary for inducing signaling and GF activity, even in the osteogenic lineage. Unlike recombinant proteins, however, HS and CS GAGs are quite heterogenous due, in large part, to post-translational addition, then removal, of sulfate groups to various positions along the GAG polymer. We have, therefore, investigated whether it would be feasible to deliver a DNA pro-drug to generate a soluble HS/CS proteoglycan in situ that would augment the activity of growth-factors, including BMP-2, in vivo.Utilizing a purified recombinant human perlecan domain 1 (rhPln.D1) expressed from HEK 293 cells with HS and CS GAGs, tight binding and dose-enhancement of rhBMP-2 activity was demonstrated in vitro. In vitro, the expressed rhPln.D1 was characterized by modification with sulfated HS and CS GAGs. Dose-enhancement of rhBMP-2 by a pln.D1 expression plasmid delivered together as a lyophilized single-phase on a particulate tricalcium phosphate scaffold for 6 or more weeks generated up to 9 fold more bone volume de novo on the maxillary ridge in a rat model than in control sites without the pln.D1 plasmid. Using a significantly lower BMP-2 dose, this combination provided more than 5 times as much maxillary ridge augmentation and greater density than rhBMP-2 delivered on a collagen sponge (InFuse™).A recombinant HS/CS PG interacted strongly and functionally with BMP-2 in binding and cell-based assays, and, in vivo, the pln.247 expression plasmid significantly improved the dose-effectiveness of BMP-2 osteogenic activity for in vivo de novo bone generation when delivered together on a scaffold as a single-phase. The use of HS/CS PGs may be useful to augment GF therapeutics, and a plasmid-based approach has been shown here to be highly effective.

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Perlecan domain V therapy for stroke: a beacon of hope?

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