Topical administration of a connexin43-based peptide augments healing of chronic neuropathic diabetic foot ulcers: A multicenter, randomized trial

Wound Repair and Regeneration

Volumn 23, Issue 2, 2015, Pages 203-212

  Grek, Christina L ^a   Prasad, G M ^b   Viswanathan, Vijay ^c   Armstrong, David G ^d   Gourdie, Robert G ^e,f   Ghatnekar, Gautam S ^a  

^a FirstString Research Inc ^*  (United States)

^b Pace Clinical Research Center   (India)

^c Department of Biochemistry and Molecular Genetics   (India)

^d UNIVERSITY OF ARIZONA COLLEGE OF MEDICINE   (United States)

^e VIRGINIA TECH CARILION SCHOOL OF MEDICINE   (United States)

^f Virginia Tech Wake Forest School of Biomedical Engineering and Sciences   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACT1 PROTEIN; CONNEXIN 43; HEMOGLOBIN A1C; UNCLASSIFIED DRUG; WOUND HEALING PROMOTING AGENT; ANTIINFECTIVE AGENT; PEPTIDE; TRAF3IP2 PROTEIN, HUMAN; TUMOR NECROSIS FACTOR RECEPTOR ASSOCIATED FACTOR;

ADULT; ANKLE BRACHIAL INDEX; ARTICLE; BACKACHE; BLISTER; CARBOXY TERMINAL SEQUENCE; CLINICAL PROTOCOL; CONTROLLED STUDY; DIABETIC FOOT; DISEASE DURATION; DRUG EFFICACY; DRUG INDUCED HEADACHE; DRUG SAFETY; EPITHELIZATION; FEMALE; FOLLOW UP; HEALING IMPAIRMENT; HEALTH CARE QUALITY; HEMOGLOBIN BLOOD LEVEL; HUMAN; IMMUNOGENICITY; LEG PAIN; MAJOR CLINICAL STUDY; MALE; MULTICENTER STUDY; PAIN INTENSITY; PNEUMONIA; PRIORITY JOURNAL; PROSPECTIVE STUDY; RANDOMIZED CONTROLLED TRIAL; RESPIRATORY TRACT INFECTION; SINGLE BLIND PROCEDURE; TOOTH PAIN; TOPICAL TREATMENT; TREATMENT OUTCOME; ULCER HEALING; WOUND COMPLICATION; CLINICAL TRIAL; DRUG EFFECTS; MIDDLE AGED; PATHOLOGY; SURGICAL WOUND INFECTION; TOPICAL DRUG ADMINISTRATION; WOUND HEALING;

ADMINISTRATION, TOPICAL; ANTI-INFECTIVE AGENTS; CONNEXIN 43; DIABETIC FOOT; FEMALE; HUMANS; MALE; MIDDLE AGED; PEPTIDES; PROSPECTIVE STUDIES; SURGICAL WOUND INFECTION; TREATMENT OUTCOME; TUMOR NECROSIS FACTOR RECEPTOR-ASSOCIATED PEPTIDES AND PROTEINS; WOUND HEALING;

EID: 84931563461     PISSN: 10671927     EISSN: 1524475X     Source Type: Journal    
DOI: 10.1111/wrr.12275     Document Type: Article

References (37)

1. International Working Group of the Diabetic Foot (IWGDF). 2014. Available at http://iwgdf.org. Accessed August 2014.
2. Game FL, Hinchliffe RJ, Apelqvist J, Armstrong DG, Bakker K, Hartemann A, et al., A systematic review of interventions to enhance the healing of chronic ulcers of the foot in diabetes. Diabetes Metab Res Rev 2012; 28 (Suppl 1): 119-41.
3. Stockl K, Vanderplas A, Tafesse E, Chang E,. Costs of lower-extremity ulcers among patients with diabetes. Diabetes Care 2004; 27: 2129-34.
4. Frykberg RG, Zgonis T, Armstrong DG, Driver VR, Giurini JM, Kravitz SR, et al., Diabetic foot disorders. A clinical practice guideline (2006 revision). J Foot Ankle Surg 2006; 45: S1-66.
5. Margolis DJ, Kantor J, Berlin JA,. Healing of diabetic neuropathic foot ulcers receiving standard treatment. A meta-analysis. Diabetes Care 1999; 22: 692-5.
6. Hinchliffe RJ, Valk GD, Apelqvist J, Armstrong DG, Bakker K, Game FL, et al., A systematic review of the effectiveness of interventions to enhance the healing of chronic ulcers of the foot in diabetes. Diabetes Metab Res Rev 2008; 24 (Suppl 1): S119-44.
7. Wang CM, Lincoln J, Cook JE, Becker DL,. Abnormal connexin expression underlies delayed wound healing in diabetic skin. Diabetes 2007; 56: 2809-17.
8. pi twb 0.35wMendoza-Naranjo A, Cormie P, Serrano AE, Wang CM, Thrasivoulou C, Sutcliffe JE, et al., Overexpression of the gap junction protein Cx43 as found in diabetic foot ulcers can retard fibroblast migration. Cell Biol Int 2012; 36: 661-7.
9. Pollok S, Pfeiffer AC, Lobmann R, Wright CS, Moll I, Martin PE, et al., Connexin 43 mimetic peptide Gap27 reveals potential differences in the role of Cx43 in wound repair between diabetic and non-diabetic cells. J Cell Mol Med 2011; 15: 861-73.
10. Brandner JM, Houdek P, Husing B, Kaiser C, Moll I,. Connexins 26, 30, and 43: differences among spontaneous, chronic, and accelerated human wound healing. J Invest Dermatol 2004; 122: 1310-20.
11. Abdullah KM, Luthra G, Bilski JJ, Abdullah SA, Reynolds LP, Redmer DA, et al., Cell-to-cell communication and expression of gap junctional proteins in human diabetic and nondiabetic skin fibroblasts: effects of basic fibroblast growth factor. Endocrine 1999; 10: 35-41.
12. Ghatnekar GS, O'Quinn MP, Jourdan LJ, Gurjarpadhye AA, Draughn RL, Gourdie RG,. Connexin43 carboxyl-terminal peptides reduce scar progenitor and promote regenerative healing following skin wounding. Regen Med 2009; 4: 205-23.
13. Gourdie RG, Ghatnekar GS, O'Quinn M, Rhett MJ, Barker RJ, Zhu C, et al., The unstoppable connexin43 carboxyl-terminus: new roles in gap junction organization and wound healing. Ann N Y Acad Sci 2006; 1080: 49-62.
14. Rhett JM, Ghatnekar GS, Palatinus JA, O'Quinn M, Yost MJ, Gourdie RG,. Novel therapies for scar reduction and regenerative healing of skin wounds. Trends Biotechnol 2008; 26: 173-80.
15. Hunter AW, Barker RJ, Zhu C, Gourdie RG,. Zonula occludens-1 alters connexin43 gap junction size and organization by influencing channel accretion. Mol Biol Cell 2005; 16: 5686-98.
16. Rhett JM, Jourdan J, Gourdie RG,. Connexin 43 connexon to gap junction transition is regulated by zonula occludens-1. Mol Biol Cell 2011; 22: 1516-28.
17. Margolis DJ, Allen-Taylor L, Hoffstad O, Berlin JA,. The accuracy of venous leg ulcer prognostic models in a wound care system. Wound Repair Regen 2004; 12: 163-8.
18. Sheehan P, Jones P, Caselli A, Giurini JM, Veves A,. Percent change in wound area of diabetic foot ulcers over a 4-week period is a robust predictor of complete healing in a 12-week prospective trial. Diabetes Care 2003; 26: 1879-82.
19. Balingit PP, Armstrong DG, Reyzelman AM, Bolton L, Verco SJ, Rodgers KE, et al., NorLeu3-A(1-7) stimulation of diabetic foot ulcer healing: results of a randomized, parallel-group, double-blind, placebo-controlled phase 2 clinical trial. Wound Repair Regen 2012; 20: 482-90.
20. Margolis DJ, Allen-Taylor L, Hoffstad O, Berlin JA,. Diabetic neuropathic foot ulcers: the association of wound size, wound duration, and wound grade on healing. Diabetes Care 2002; 25: 1835-9.
21. Greer N, Foman NA, Macdonald R, Dorrian J, Fitzgerald P, Rutks I, et al., Advanced wound care therapies for nonhealing diabetic, venous, and arterial ulcers: a systematic review. Ann Intern Med 2013; 159: 532-42.
22. Wieman TJ, Smiell JM, Su Y,. Efficacy and safety of a topical gel formulation of recombinant human platelet-derived growth factor-BB (becaplermin) in patients with chronic neuropathic diabetic ulcers. A phase III randomized placebo-controlled double-blind study. Diabetes Care 1998; 21: 822-7.
23. Veves A, Falanga V, Armstrong DG, Sabolinski ML, Apligraf Diabetic Foot Ulcer S. Graftskin, a human skin equivalent, is effective in the management of noninfected neuropathic diabetic foot ulcers: a prospective randomized multicenter clinical trial. Diabetes Care 2001; 24: 290-5.
24. Marston WA, Hanft J, Norwood P, Pollak R, Dermagraft Diabetic Foot Ulcer Study G. The efficacy and safety of Dermagraft in improving the healing of chronic diabetic foot ulcers: results of a prospective randomized trial. Diabetes Care 2003; 26: 1701-5.
25. Pfenniger A, Wohlwend A, Kwak BR,. Mutations in connexin genes and disease. Eur J Clin Invest 2011; 41: 103-16.
26. O'Quinn MP, Palatinus JA, Harris BS, Hewett KW, Gourdie RG,. A peptide mimetic of the connexin43 carboxyl terminus reduces gap junction remodeling and induced arrhythmia following ventricular injury. Circ Res 2011; 108: 704-15.
27. Bobbie MW, Roy S, Trudeau K, Munger SJ, Simon AM, Roy S,. Reduced connexin 43 expression and its effect on the development of vascular lesions in retinas of diabetic mice. Invest Ophthalmol Vis Sci 2010; 51: 3758-63.
28. Acosta JB, del Barco DG, Vera DC, Savigne W, Lopez-Saura P, Guillen Nieto G, et al., The pro-inflammatory environment in recalcitrant diabetic foot wounds. Int Wound J 2008; 5: 530-9.
29. Qiu C, Coutinho P, Frank S, Franke S, Law LY, Martin P, et al., Targeting connexin43 expression accelerates the rate of wound repair. Curr Biol 2003; 13: 1697-703.
30. Mori R, Power KT, Wang CM, Martin P, Becker DL,. Acute downregulation of connexin43 at wound sites leads to a reduced inflammatory response, enhanced keratinocyte proliferation and wound fibroblast migration. J Cell Sci 2006; 119: 5193-203.
31. Kretz M, Maass K, Willecke K,. Expression and function of connexins in the epidermis, analyzed with transgenic mouse mutants. Eur J Cell Biol 2004; 83: 647-54.
32. Coutinho P, Qiu C, Frank S, Tamber K, Becker D,. Dynamic changes in connexin expression correlate with key events in the wound healing process. Cell Biol Int 2003; 27: 525-41.
33. Contreras JE, Sanchez HA, Veliz LP, Bukauskas FF, Bennett MV, Saez JC,. Role of connexin-based gap junction channels and hemichannels in ischemia-induced cell death in nervous tissue. Brain Res Brain Res Rev 2004; 47: 290-303.
34. Goubaeva F, Mikami M, Giardina S, Ding B, Abe J, Yang J,. Cardiac mitochondrial connexin 43 regulates apoptosis. Biochem Biophys Res Commun 2007; 352: 97-103.
35. Guo YN, Wang JC, Cai GY, Hu X, Cui SY, Lv Y, et al., AMPK-mediated downregulation of connexin43 and premature senescence of mesangial cells under high-glucose conditions. Exp Gerontol 2014; 51: 71-81.
36. Mustoe T,. Understanding chronic wounds: a unifying hypothesis on their pathogenesis and implications for therapy. Am J Surg 2004; 187: 65S-70S.
37. Dinh T, Tecilazich F, Kafanas A, Doupis J, Gnardellis C, Leal E, et al., Mechanisms involved in the development and healing of diabetic foot ulceration. Diabetes 2012; 61: 2937-47.