Phase I trial on the safety of topical rhVEGF on chronic neuropathic diabetic foot ulcers

Hanft, Jason R.; Pollak, Richard; Barbul, Adrian; Gils, Carolien Van; Kwon, Paul; Gray, Sharon; Lynch, Catherine; Semba, Charles P.; Breen, Thomas

doi:10.12968/jowc.2008.17.1.27917

Cited by 136 publications

(153 citation statements)

References 31 publications

Supporting

Mentioning

147

Contrasting

Unclassified

Order By: Relevance

“…The use of a single mouse model for the analysis of therapeutic efficacy could be seen as a potential limitation of our study. However, the db/db diabetic mice are those used most often as a model of human diabetic chronic wounds (87), and the genetically modified db/db diabetic mouse has been used previously to support clinical trial development with other molecules (88).…”

Section: Discussionmentioning

confidence: 99%

Diabetic wound regeneration using peptide-modified hydrogels to target re-epithelialization

Xiao

Reis

Feric

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

127

156

View full text Add to dashboard Cite

There is a clinical need for new, more effective treatments for chronic wounds in diabetic patients. Lack of epithelial cell migration is a hallmark of nonhealing wounds, and diabetes often involves endothelial dysfunction. Therefore, targeting re-epithelialization, which mainly involves keratinocytes, may improve therapeutic outcomes of current treatments. In this study, we present an integrin-binding prosurvival peptide derived from angiopoietin-1, QHREDGS (glutamine-histidine-arginine-glutamic acid-aspartic acid-glycine-serine), as a therapeutic candidate for diabetic wound treatments by demonstrating its efficacy in promoting the attachment, survival, and collective migration of human primary keratinocytes and the activation of protein kinase B Akt and MAPK p42/44 . The QHREDGS peptide, both as a soluble supplement and when immobilized in a substrate, protected keratinocytes against hydrogen peroxide stress in a dose-dependent manner. Collective migration of both normal and diabetic human keratinocytes was promoted on chitosan-collagen films with the immobilized QHREDGS peptide. The clinical relevance was demonstrated further by assessing the chitosan-collagen hydrogel with immobilized QHREDGS in full-thickness excisional wounds in a db/db diabetic mouse model; QHREDGS showed significantly accelerated and enhanced wound closure compared with a clinically approved collagen wound dressing, peptide-free hydrogel, or blank wound controls. The accelerated wound closure resulted primarily from faster re-epithelialization and increased formation of granulation tissue. There were no observable differences in blood vessel density or size within the wound; however, the total number of blood vessels was greater in the peptide-hydrogeltreated wounds. Together, these findings indicate that QHREDGS is a promising candidate for wound-healing interventions that enhance reepithelialization and the formation of granulation tissue.

show abstract

Section: Discussionmentioning

confidence: 99%

Diabetic wound regeneration using peptide-modified hydrogels to target re-epithelialization

Xiao

Reis

Feric

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

127

156

View full text Add to dashboard Cite

show abstract

“…Increasing VEGF should enhance angiogenesis (and vasculogenesis), resulting in the formation of more blood vessels and, as a result, improve blood flow in the area of the wound. Clinical trials have been performed using topical recombinant human VEGF (telburmin, Genentech, South San Fransisco, CA) on diabetic foot ulcers; 106 however, even though positive trends in incidence of complete healing and time to complete healing were reported, no published information is available beyond these phase I studies.…”

Section: Future Directions Altering Vegf For Therapeutic Purposesmentioning

confidence: 99%

Vascular Endothelial Growth Factor and Angiogenesis in the Regulation of Cutaneous Wound Repair

Johnson

Wilgus

2014

Advances in Wound Care

755

484

View full text Add to dashboard Cite

“…[7][8][9] For example, the development of vascular endothelial growth factor (VEGF) was halted in phase II clinical trials, despite its positive safety profile. 10 Due to the short half-life of VEGF (*30 min 11 ), this therapy required frequent administration to yield only a modest effect on neovascularization in injured tissues, 6 and it was deemed unsuitable as a cost-effective drug strategy. Similarly, platelet-derived growth factor (PDGF) is currently approved as a drug to accelerate wound healing, in part, by enhancing cell migration and matrix synthesis.…”

Section: Introductionmentioning

confidence: 99%

Multivalent Conjugates of Sonic Hedgehog Accelerate Diabetic Wound Healing

Han

Layman

Rode

et al. 2015

Tissue Engineering Part A

View full text Add to dashboard Cite

Despite their preclinical promise, few recombinant growth factors have been fully developed into effective therapies, in part, due to the short interval of therapeutic activity after administration. To address this problem, we developed nanoscale polymer conjugates for multivalent presentation of therapeutic proteins that enhance the activation of targeted cellular responses. As an example of this technology, we conjugated multiple Sonic hedgehog (Shh) proteins onto individual hyaluronic acid biopolymers to generate multivalent protein clusters at defined ratios (i.e., valencies) that yield enhanced Shh pathway activation at equivalent concentrations relative to unconjugated Shh. In this study, we investigated whether these multivalent conjugates (mvShh) could be used to improve the therapeutic function of Shh. We found that a single treatment with mvShh significantly accelerated the closure of full-thickness wounds in diabetic (db/db) mice compared to either an equivalent dose of unconjugated Shh or the vehicle control. Furthermore, we identified specific indicators of wound healing in fibroblasts and endothelial cells (i.e., transcriptional activation and cell migration) that were activated by mvShh in vitro and at concentrations approximately an order of magnitude lower than the unconjugated Shh. Taken together, our findings suggest that mvShh conjugates exhibit greater potency to activate the Shh pathway, and this multivalency advantage improves its therapeutic effect to accelerate wound closure in a diabetic animal model. Our strategy of multivalent protein presentation using nanoscale polymer conjugates has the potential to make a significant impact on the development of protein-based therapies by improving their in vivo performance.

show abstract

Phase I trial on the safety of topical rhVEGF on chronic neuropathic diabetic foot ulcers

Abstract: The topical application of telbermin 72 microg/cm2 three times a week for up to six weeks appeared to be well tolerated. Further studies are required to characterise the safety/efficacy of telbermin more completely.

Cited by 136 publications

References 31 publications

Diabetic wound regeneration using peptide-modified hydrogels to target re-epithelialization

Diabetic wound regeneration using peptide-modified hydrogels to target re-epithelialization

Vascular Endothelial Growth Factor and Angiogenesis in the Regulation of Cutaneous Wound Repair

Multivalent Conjugates of Sonic Hedgehog Accelerate Diabetic Wound Healing

Contact Info

Product

Resources

About