Hot Topics in Wound Care 2011

Transcription

1 Hot Topics in Wound Care 2011 Thomas E. Serena MD FACS FACHM MAPWCA Founder & Medical Director - Penn North Centers for Advanced Wound Care Chief Medical Officer - SerenaGroup Scientific Director - New Bridge Medical Research Vice President - American College of Hyperbaric Medicine CEO - SERENA GROUP Outline A Novel Pharmaceutical that blocks Gap junctions and controls Intercellular Communication Diagnostics: A tectonic shift in wound care A Designer matrix: growth factors and extracellular scaffold. Insert video Current Practice 1

2 Developing a point of care wound diagnostic Traditional pathway for Diagnostics (e.g. HbA1c, Creatinine, CRP): Proove science behind test* Develop validated laboratory test Develop validated point of care test Systagenix development of point of care test for elevated protease activity: - Proove science behind test* - Develop validated point of care test * Clinical range, levels associated with condition of interest (e.g. Kidney damange, lack of glyceamic control, infection, stalled wound healing) Proteases in Chronic Wounds Proteases are in excess in chronic wounds Inflammatory Proteases Predominate Protease Activity (RFU/min/mg) Elastase Venous Leg Ulcers Diabetic Foot Ulcers Pressure Sores MMPs MMP level (ng/ml/mg) MMP-9 MMP-8 MMP-3 MMP-2 MMP-1 Chronic fluid Published Data: Cullen, B. et al., (2002) Wound Rep Reg. 10: Vasculitis 2

3 Can you predict the level of proteases based on clinical examination? Positive or Negative Positive or Negative 63 yr old with a Venous Leg ulcer of 6 months duration. Low level of exudate. 3

4 Clinical Range Total Inflammatory Protease Activity Total Inflammatory Protease Activity (184 clinical samples) , Sample Number Activity Levels associated with stalled wound healing 140 Total Inflammatory Protease Activity (21 DFU, PU, VLU samples) Total Inflammatory Protease Activity Median value 5 0 Non-Healing Healing Point of Care Diagnostics 4

5 Biofilm New gel could heal wounds 5 times faster LONDON (AP) For three years, Connie McPherson had debilitating leg ulcers that were so painful she sometimes.. 5

6 Figure 1 Connexins and the formation of Gap Junctions Journal of Investigative Dermatology (2007) 127, doi: /sj.jid Figure 4 Connexin Distribution in the Skin Journal of Investigative Dermatology (2007) 127, doi: /sj.jid Immunohistochemisty Cx43 (skin): normal Down regulated Normal Arrow is wound edge; Cx43 is green-speckled fluorescence Bright lines in rat are auto-fluorescence of keratin 6

7 Connexin 43 in Normal Wound Healing (Skin) After wounding: Decreased Cx43 expression in the cells on the margin of the wound within hours. Up-regulation of Cx43 in vessels near wounds Bystander Death and Lesion Spread Gap junctions also send signals to each other and ECM Some of these are death signals (e.g., calcium) Dying cells can induce apoptosis in neighboring cells. Mediated by gap junctions including Cx43 Cell death is directly proportion to the number and density of gap junctions within the dying cells This can result in bystander cell death and lesion spread Lin JH, Weigel H, Cotrina ML, Liu S, Bueno E, Hansen AJ, et al.. Gap junction-mediated propagation and amplification of cell injury. Nat Neurosci 1998;1(6): Is Connexin 43 a Potential Target for Accelerated Healing of Chronic Wounds? 7

8 NEXAGON is Nexagon A selective inhibitor of Cx43 expression An unmodified antisense DNA oligonucleotide that binds to the Cx43 mrna Binding leads to destruction of the mrna and thereby transient down-regulation of the protein in cells until antisense is destroyed The effect on Cx43 is temporary depending on delivery method (<48hrs) Wound healing using Cx43 Antisense gel 6hr 1day 2day 7day Neonatal mice Nexagon Control Incisional wound Cx43 ASN gel applied after wounding Similar findings in adult mice Qiu et al. Curr Biol 2003 Connexin 43 and Chronic Wound Healing 8

9 Human Clinical Studies Cx43 INTACT SKIN & VENOUS LEG ULCER LOW POWER Venous Leg Ulcer Intact skin 1mm W 1mm 26 Cx43 INTACT SKIN & VENOUS LEG ULCER HIGH POWER Intact skin Wound edge 4mm from edge Epidermis fold increase in Cx43 Dermis 41 fold increase in Cx

10 Cx43 INTACT DIABETIC SKIN & CHRONIC WOUND Intact diabetic skin Chronic diabetic wound Epidermis 13 fold increase in Cx43 Dermis 466 fold increase in Cx43 28 Cx43 in a 2.5 cm CHRONIC WOUND BIOPSY W 5 mm 29 Initial Biopsy Conclusions Connexin 43 increased in wound edge of the 4 different chronic wound etiologies examined so far: Venous, diabetic, vasculitic and pressure ulcers Connexin 43 grossly increased in epidermis compared to normal skin More thickened epidermis expressing Cx43 More Cx43 per cell Connexin 43 grossly increased in dermis Manuscript in progress 10

11 All my trials and tribulations NOVEL Trial Phase IIa Indication: Chronic venous leg ulcers 4-Week, three arm trial: Vehicle, low-dose and high-dose anti-connexon (Nexagon ) (1:1:1) Endpoints: Safety; Surface Area Reduction; Percent Wounds Fully Closed over four weeks 98 patients randomized in New Zealand and USA Percent Complete Healers* Percentage Surface Area Reduction** Per Protocol Intent-to-Treat Per Protocol Intent-to-Treat 100 µm 31% 28% - 69% - 68% 30 µm 17% 18% - 61% - 59% 0 µm 6% 6% - 59% - 58% 100 µm vs. Vehicle p = p = p = 0.16 p =

12 Percent Complete Healers at Percentage Surface Area Reduction at 4 Weeks 4 Weeks PP Population (With and Without Erie) PP Population (With Erie) PP Population (Without Erie) 31% - 69% - 74% 17% - 61% - 65% 6% - 59% - 61% p = p = 0.16 p =

13 Farm Sheep- New Zealand. Equine Pericardium-DFU Trial. Porcine. Synthetic- DFU Why can t we put cells or growth factors in these matrix products Designer Scaffolds 13

14 Vitronectin-insulin growth factor complex Vitronectin (VN) improves the delivery of growth stimulating insulin-like growth factors (IGFs) to their receptors, type-1 IGF receptors on cell surfaces. The complex promotes healing by replacing the damaged extracellular matrix. 14