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• W2023307607 abstract "Venous leg ulcers are a prevalent nonhealing wound of the lower extremity. Although topically applied growth factors successfully improve wound repair in animal studies, similar studies on humans with venous leg ulcers have not been successful. This study was designed to evaluate the acute safety and biologic feasibility of peri-ulcer injection of a replication-incompetent adenoviral construct expressing platelet-derived growth factor-β (PDGF-β). In this phase I study, we demonstrate the initial safety, feasibility, and biologic plausibility of using H5.020CMV.PDGF-β to treat venous leg ulcer disease. Venous leg ulcers are a prevalent nonhealing wound of the lower extremity. Although topically applied growth factors successfully improve wound repair in animal studies, similar studies on humans with venous leg ulcers have not been successful. This study was designed to evaluate the acute safety and biologic feasibility of peri-ulcer injection of a replication-incompetent adenoviral construct expressing platelet-derived growth factor-β (PDGF-β). In this phase I study, we demonstrate the initial safety, feasibility, and biologic plausibility of using H5.020CMV.PDGF-β to treat venous leg ulcer disease. Chronic wounds have become a major health concern for the United States and abroad. In the United States alone, chronic wounds cost the health-care system ~$9.7 billion annually.1Ruckley CV Socioeconomic impact of chronic venous insufficiency and leg ulcers.Angiology. 1997; 48: 67-69Crossref PubMed Scopus (323) Google Scholar,2Bickers DR Lim HW Margolis D Weinstock MA Goodman C Faulkner E et al.The burden of skin diseases: 2004 a joint project of the American Academy of Dermatology Association and the Society for Investigative Dermatology.J Am Acad Dermatol. 2006; 55: 490-500Abstract Full Text Full Text PDF PubMed Scopus (574) Google Scholar A large portion of these wounds are localized to the lower extremities, where their prevalence has been estimated at 0.2–2% of the adult population.3Coon WW Willis PW Keller JB Venous thromboembolism and other venous disease in the Tecumseh community health study.Circulation. 1973; 48: 839-846Crossref PubMed Scopus (479) Google Scholar,4Hallbook T Leg ulcer epidemiology.Acta Chir Scand. 1988; 544: 17-20Google Scholar Multiple etiologies have been implicated as a cause for lower extremity wounds, including venous disease, arterial insufficiency, and insensate neuropathy.4Hallbook T Leg ulcer epidemiology.Acta Chir Scand. 1988; 544: 17-20Google Scholar,5Phillips TJ Chronic cutaneous ulcers: etiology and epidemiology.J Invest Dermatol. 1994; 102: 38S-41SCrossref PubMed Scopus (104) Google Scholar Venous disease, being the most common cause, is estimated to be responsible for 40–70% of chronic lower extremity wounds. Furthermore, it is believed that between 500,000 and 2 million Americans suffer from venous leg ulcer disease.3Coon WW Willis PW Keller JB Venous thromboembolism and other venous disease in the Tecumseh community health study.Circulation. 1973; 48: 839-846Crossref PubMed Scopus (479) Google Scholar,5Phillips TJ Chronic cutaneous ulcers: etiology and epidemiology.J Invest Dermatol. 1994; 102: 38S-41SCrossref PubMed Scopus (104) Google Scholar Successful treatment of venous leg ulcer disease has been difficult to achieve. Lower limb compression has been the standard of care for these patients, but unfortunately, is too often unsuccessful. Additionally, to achieve optimal results, this technique requires a prolonged 24-week treatment period, and even then only achieves success rates between 30 and 70% (refs. 6O'Meara S Tierney J Cullum N Bland JM Franks PJ Mole T et al.A systematic review of compression treatment for venous leg ulcers.BMJ. 2009; 3385: 1047-1063Google Scholar,7Skene AI Smith JM Doré CJ Charlett A Lewis JD Venous leg ulcers: a prognostic index to predict time to healing.BMJ. 1992; 305: 1119-1121Crossref PubMed Scopus (158) Google Scholar,8Falanga V Margolis D Alvarez O Auletta M Maggiacomo F Altman M et al.Rapid healing of venous ulcers and lack of clinical rejection with an allogeneic cultured human skin equivalent. Human Skin Equivalent Investigators Group.Arch Dermatol. 1998; 134: 293-300Crossref PubMed Scopus (579) Google Scholar). Due to the suboptimal results obtained from leg compression therapy alone, alternative methods to treat nonhealing venous leg ulcer disease have been explored. One promising alternative is the administration of growth factors to the wound site, which are known to be important for wound healing. One particular growth factor of interest in treating chronic nonhealing wounds is platelet-derived growth factor (PDGF). This protein is normally deposited into tissue in large quantities by degranulating platelets shortly after injury, where it is known to assist in wound repair.9Clark RAF (1996). Wound repair: overview and general considerations In: Clark RAF (ed). The Molecular and Cellular Biology of Wound Repair, 2 edn. Plenum: New York. pp. 3–50Google Scholar,10Martin P Wound healing—aiming for perfect skin regeneration.Science. 1997; 276: 75-81Crossref PubMed Scopus (3791) Google Scholar PDGF is also normally secreted by several other cell lines active in wound repair, such as macrophages, endothelial cells, fibroblasts, and keratinocytes.11Danilenko DM Ring BD Tarpley JE Morris B Van GY Morawiecki A et al.Growth factors in porcine full and partial thickness burn repair. Differing targets and effects of keratinocyte growth factor, platelet-derived growth factor-BB, epidermal growth factor, and neu differentiation factor.Am J Pathol. 1995; 147: 1261-1277PubMed Google Scholar When supplemented onto wounds in various animal models, PDGF has been shown to increase the rate at which wounds heal.10Martin P Wound healing—aiming for perfect skin regeneration.Science. 1997; 276: 75-81Crossref PubMed Scopus (3791) Google Scholar,12Pierce GF Mustoe TA Pharmacologic enhancement of wound healing.Annu Rev Med. 1995; 46: 467-481Crossref PubMed Scopus (186) Google Scholar,13Pierce GF Tarpley JE Tseng J Bready J Chang D Kenney WC et al.Detection of platelet-derived growth factor (PDGF)-AA in actively healing human wounds treated with recombinant PDGF-BB and absence of PDGF in chronic nonhealing wounds.J Clin Invest. 1995; 96: 1336-1350Crossref PubMed Scopus (199) Google Scholar,14Beer HD Longaker MT Werner S Reduced expression of PDGF and PDGF receptors during impaired wound healing.J Invest Dermatol. 1997; 109: 132-138Abstract Full Text PDF PubMed Scopus (202) Google Scholar PDGF administration has also been used in humans and approved by the US Food and Drug Administration (FDA) to treat diabetic foot ulcers.15Wieman 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: 822-827Crossref PubMed Scopus (558) Google Scholar Additionally, trials using PDGF to treat venous leg ulcers have resulted in FDA approval. Previous studies have attempted to treat venous leg ulcer disease by using various topically administered growth factors including PDGF, acidic fibroblast growth factor, basic fibroblast growth factor, insulin-like growth factor, epidermal growth factor, keratinocyte growth factor, transforming-α, and transforming growth factor-β. Many of these studies, however, have gone unpublished due to lack of efficacy.16Falanga V Eaglstein WH Bucalo B Katz MH Harris B Carson P Topical use of human recombinant epidermal growth factor (h-EGF) in venous ulcers.J Dermatol Surg Oncol. 1992; 18: 604-606Crossref PubMed Scopus (183) Google Scholar The reasons for failed efficacy of these novel pharmaceuticals are not clear but may be due to problems in growth factor penetration into the wound. Without adequate penetration, these growth factors may not reach their target cells and consequently fail to initiate the wound healing process. In addition, the application of growth factors is often daily, which interrupts the use of standard limb compression therapy. Recently, the use of gene transfer to introduce PDGF into animal wounds has been shown to be superior to topical application.17Crombleholme TM Adenoviral-mediated gene transfer in wound healing.Wound Repair Regen. 2000; 8: 460-472Crossref PubMed Google Scholar,18Liechty KW Sablich TJ Adzick NS Crombleholme TM Recombinant adenoviral mediated gene transfer in ischemic impaired wound healing.Wound Repair Regen. 1999; 7: 148-153Crossref PubMed Scopus (37) Google Scholar,19Sylvester KG Nesbit M Radu A Herlyn M Adzick NS Crombleholme TM Adenoviral-mediated gene transfer in wound healing: acute inflammatory response in human skin in the SCID mouse model.Wound Repair Regen. 2000; 8: 36-44Crossref PubMed Google Scholar,20Gruss CJ Satyamoorthy K Berking C Lininger J Nesbit M Schaider H et al.Stroma formation and angiogenesis by overexpression of growth factors, cytokines, and proteolytic enzymes in human skin grafted to SCID mice.J Invest Dermatol. 2003; 120: 683-692Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar It is our contention that the use of cytokine growth factors should augment the healing of chronic wounds and that topical application is an ineffective method of application. This study was designed to evaluate the acute safety and biologic feasibility of peri-ulcer injection of a replication-incompetent adenoviral construct expressing PDGF-β under the control of the cytomegalovirus (CMV) promoter and early enhancer. We discussed the study with 247 subjects to determine their interest and obtained consent from 26 subjects, who were formally screened. During this process, 11 were found to be ineligible for the following reasons: four had wounds smaller than 5 cm2, two were seropositive for hepatitis C, one did not complete all screening tests, one subject had an erythrocyte sedimentation rate > 60; one subject had hemoglobin <10, one subject had a hemoglobin <10 and an erythrocyte sedimentation rate >60, and 1 individual had a positive antinuclear antibody. The average age of the participants was 46.4 years (SD 6.9) with a median age of 48 years. Of the 15 subjects, 11 (73 %) were male and 9 (60%) were Caucasian. The average weight was 126.2 kg (SD 59.8) and the median weight was 115 kg. Twelve subjects (80%) had more than one wound and 10 (67%) had a history of previous wounds. At screening, the average wound was 24.4 cm2 (SD 21.5) and the median wound size was 19.5 cm2. Mean wound size for each dose-group is described in Table 1 and for each participant in Table 2. The average wound duration was 24.9 months (SD 31.5) and the median wound duration was 12 months. Twelve subjects had additional wounds that were usually smaller and of shorter duration.Table 1Averaged by dose groupDoseNN healed 6 monthsInitial wound sizeEnd wound sizeaAll wounds measured in cm2.Percentage change areaLog healing rate13317.6 (6.0)5.4 (2.8)53.2 (24.3)0.07 (0.06)23135.3 (19.1)22.5 (14.4)51.7 (16.4)0.03 (0.02)3319.8 (2.0)2.3 (2.2)79.2 (18.7)0.12 (0.04)46329.7 (9.5)23.4 (6.7)21.0 (11.3)0.01 (0.004)End wound size by day 28 unless subject healed. If they healed then wound was measured at day 21.a All wounds measured in cm2. Open table in a new tab Table 2Data for each subjectDoseInitial wound size-cm2End wound sizeaAll wounds measured in cm2.Primary study daysHealed by 6 monthsPercentage change areaLog healing rate116.365.4728113.990.0052119.510.228147.690.02331270.621197.780.1814228.316.628041.340.0195271.3449.9428030.000.013626.15128183.740.065735.90.221096.610.1618312.10.128199.170.1719311.56.728041.740.01910410.86.928036.110.0161145.62.928048.210.02412463.137.528140.570.01813453.542.828120.000.00814420.518.82808.290.00315424.531.2280-27.34-0.009a All wounds measured in cm2. Open table in a new tab End wound size by day 28 unless subject healed. If they healed then wound was measured at day 21. In general, the injection was well tolerated and the subjects showed improvement in their wounds over the 28 days of the primary study. No subjects reported pain from the injection. No signs of local wound infection, wound erythema, or cellulitis were observed as a consequence of the injection. Wound improvement was noted by several parameters during the first 28 days of the study. Wound pain was noted by 13 of 15 subjects at baseline. By day 28 no one reported an increase in pain; by week 28, only 3 of 15 still reported pain and two of these subjects noticed much less pain. For all subjects, granulation tissue increased during the study period. Granulation tissue was often exuberant, it often filled the wound (i.e., was not just present in the site of injection), and, between days 7 and 14, for those in dose-group 1–3, the wounds often superficially bled during dressing changes. All biopsy sites healed without complication. A decrease in wound size between baseline and day 28 was noted in 14 of 15 subjects (93%). The overall mean and median percentage changes between baseline and day 28 were 45.2% (SD 36.2) and 41.3% (25%, 75%:20.0%, 83.7%), respectively, and the mean and median log healing rates were 0.048 (SD 0.065) and 0.019 (25%, 75%:0.008, 0.065), respectively (Tables 1 and 2). No statistically significant dose by “wound size change” effect was noted (percentage change, P = 0.1047 and log healing rate, P = 0.1235, respectively). By day 28 two subjects healed and at the end of 24 weeks of follow-up seven more subjects (47%) were found to have healed. Many subjects had more than one wound (12 of 15, 80%). Only the target wound was treated (largest and oldest eligible wound). For four of these multiwound subjects, a total of seven nontarget wounds healed. Based on our reference laboratory's criteria there were several laboratory abnormalities, which in general were expected. Abnormalities were noted before the experimental injection (screening and day 1) as well as days 3, 7, 14, and 28. The laboratory results most frequently reported as abnormal included: values obtained as part of complete blood count or differential, lactate dehydrogenase, glucose (in a subject with a history of diabetes), erythrocyte sedimentation rate, chloride, or CO2. One subject, in group 4, had detectable rheumatoid factor (RF) titers. This subject had trace RF titers at baseline (37 IU/ml), a low level positive at day 28 (105 IU/ml), and negative titers at month 3 (<30 IU/ml). No signs or symptoms consistent with a rheumatologic illness were noted. This finding could have represented dose-limiting toxicity (DLT). By design, H5.020CMV.PDGF-B is an adenovirus (H5) that cannot replicate. Subjects were tested at day 3, 7, 14, 21, and 28 with samples from blood, wound swabs, and bandage swabs for the presence of this virus and its ability to replicate. As expected, the adenovirus could not be cultured from any of these specimens (i.e., H5 adenovirus could not replicate and did not gain this ability after exposure to the study subjects). In total, using PCR probes, 7 of 15 subjects in 10 out of 75 specimens revealed viral DNA on the wound or on the wound-exposed bandage. All positive tests occurred at days 3 or 7. No subjects at dose 1 had a positive test. One of three subjects from dose-level 2, three of three subjects from dose-level 3, and three of six subjects from dose-level 4 had positive tests. Adenovirus DNA was noted on 5 day three wounds, 3 day three bandages, and 2 day seven wounds. Antibodies to H5 were noted in all 14 subjects. Eight of 15 had antibodies at screening. All had antibodies at month 3. The largest increases, some greater than 100-fold, were noted from the subjects that had the highest H5 antibodies at baseline and these subjects were distributed across all dose groups. It is important to realize that while this test was developed specifically to measure adenovirus H5 antibodies, the assay does crossreact and measure antibody responses to wild-type adenovirus, too. Three of 14 subjects had measurable antibodies to PDGF-BB (optical density of >0.1 at a dilution of 1:100). These were single subjects in dose groups 1, 3, and 4. The antibodies persisted to a dilution of 1:400. Their titers were undetectable at week 6. By their sixth month of care, two of these subjects healed. One of these subjects also had detectable RF titers. To assess the presence of adenoviral DNA in the wound bed, we used DNA in situ hybridization to detect the CMV promoter within the adenoviral genome. Tissue biopsies before adenoviral administration at day 1 and following adenoviral administration at days 3 and 28 were analyzed. As shown in Figure 1, adenoviral DNA was not detected before adenoviral administration at day 1. However, at day 3 adenoviral DNA was detected in both the ulcer bed and keratinocyte layer. Biopsies taken at day 28 postadenoviral injection were also found to be negative for adenoviral DNA. An important sign of wound healing is the creation of new blood vessels, or neovascularization, within the wound. To assess the degree of neovascularization, we used an endothelial cell–specific antibody to CD31 for labeling capillaries within the ulcer. These labeled cells were then quantified per high power field (HPF, ×400) in each of four quandrants within the wound biopsy as shown in Figure 2. A representative patient biopsy at days 1, 3, and 28 using CD31 immunohistochemistry can be seen in Figure 3. The average number of CD31+ staining vessels were found to be 3.8 (SD 0.9), 5.2 (SD 2.3), and 4.6 (SD 1.7) on days 1, 3, and 28, respectively (P = 0.41). Although a trend was noted comparing day 1 to days 2 or 28 (P = 0.06 and 0.09, respectively). The number of vessels noted did vary by region in that more vessels were counted in the subepidermal superficial quadrant than the others (P < 0.0001, all other comparisons P > 0.30). There was no apparent effect of increasing H5 adenovirus dose on CD31+ staining vessels.Figure 3To assess wound neovascularization after administration of H5.020CMV.PDGF-β, we immunostained tissue biopsies for an endothelial specific antigen CD31 and quantified the number of positive staining vessels per HPF at (a) day 1, (b) day 3, and (c) day 28. Bar = low power: 500 µm, high power: 150 µm. CMV, cytomegalovirus; HPF, high power field; PDGF-β, platelet-derived growth factor-β.View Large Image Figure ViewerDownload Hi-res image Download (PPT) To determine whether the administration of the adenoviral construct caused an inflammatory response within the injected tissue, the number of cells expressing the common leukocyte antigen (CD45) was quantified per HPF using immunohistochemistry. The average number of CD45+ cells noted per HPF on days 1, 3, and 28, respectively, was 12.6 (SD 7.0), 11.7 (SD 7.5), and 13.3 (SD 7.4). This can be seen in Figure 4, from a representative patient biopsy at days 1, 3, and 28. These values were found not to vary significantly by day or location (P > 0.30), suggesting no increased inflammatory response after injection of H5.020CMV.PDGF-β. Recruitment of bone marrow–derived stem cells to sites of ischemia is known to be important for normal wound healing. To determine whether the delivery of Ad-PDGF-B caused an increase in the recruitment of CD133+ cells, an antigen known to be expressed on endothelial progenitor cells, we quantified the number of these cells within a section of wound biopsy per HPF. The average number of CD133+ cells on days 1, 3, and 28 were 3.8 (SD 0.6), 5.2 (SD 0.8), and 4.6 (SD 1.4), respectively. This can be seen in Figure 5, from a representative patient biopsy at days 1, 3, and 28. The number of cells did not vary by region (P = 0.78) but did vary by day (P = 0.0023). This finding was primarily due to differences between day 1 and day 2 (Sidak adjusted P = 0.0015). Seventeen adverse events (AEs) were reported during the primary portion of the study. The most frequently reported AEs were related to pre-existing illness such as hypertension or diabetes (four reports each) as well as single reports for others. None of the AEs were thought to be related to the study. No serious AEs were noted during the initial 28-day postinjection follow-up. One serious AE was noted ~5 months postinjection. At this time a study subject was hospitalized for endocarditis. He initially appeared to recover and his wound healed. However, he died of a cardiovascular cause 11 months after injection. The goals of this study was to evaluate the acute safety of a wound-edge injection of H5.020CMV.PDGF-B and the biologic feasibility of using H5.020CMV.PDGF-B to treat patients with chronic venous leg ulcers while they receive limb compression therapy. In general, the injections were well tolerated and subjects were able to use a compression bandage during the 28 days of the initial study period. Only one individual in the study may have exhibited DLT based on the conversion of a trace positive to truly positive RF serology, which then resolved without clinical significance. Shortly after this subject was enrolled, the inclusion and exclusion criteria of the study were modified to prevent the enrollment of a subject with a slightly positive RF serology. In our early phase gene transfer study of H5.020CMV.PDGF-B, because of a lack of measured DLT, by default our maximally tolerated dose was dose-level 4. We were also able to demonstrate that H5.020CMV.PDGF-B was able to transfect cells in the wound. Transfection with H5.020CMV.PDGF-B resulted in the migration of endothelial precursor cells to the wound and the formation of granulation tissue. The injection of H5.020CMV.PDGF-β also resulted in a decrease in the overall size of the target wound by day 28 in 14 of 15 subjects. Although we found very few signs of systemic toxicity, it is possible that the adenoviral injection had a systemic effect based on the observation that “uninjected” parts of the target wound improved as did nontarget not injected wounds on the few subjects with additional wounds. Our clinical observations of improved wound healing and the presence of granulation tissue have also been reported with topical recombinant human PDGF.15Wieman 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: 822-827Crossref PubMed Scopus (558) Google Scholar In addition, although this may have been related to a lack of sensitivity of our assay, we found an antibody response to H5 (our adenoviral vector) in most subjects. Finally, antibodies were found to develop against PDGF in a few subjects that later resolved, but again our test was relatively nonspecific. Finally, based on all of our findings, the greatest effect from a single injection of H5.020CMV.PDGF-β may have been in dose groups 2 or 3. Several investigators have previously demonstrated that improvements in wound size by the fourth week of care can be used to predict that a venous leg ulcer will heal by the 16th to 24th week of care, which is the usual length of a trial to study venous leg ulcers.21Guidance for Industry: Chronic Cutaneous Ulcer and Burn Wounds-developing Products for Treatment (2006). Food and Drug Administration. pp. 1–18Google Scholar,22Kantor J Margolis DJ Expected healing rates for chronic wounds.Wounds. 2000; 12: 155-158Google Scholar For this study, we used previously validated historical comparisons based on surrogate markers for a healed wound by the 24th week of care in order to predict who might have healed.23Gelfand JM Hoffstad O Margolis DJ Surrogate endpoints for the treatment of venous leg ulcers.J Invest Dermatol. 2002; 119: 1420-1425Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar Seventy-three percent of our subjects had wound changes consistent with healing.23Gelfand JM Hoffstad O Margolis DJ Surrogate endpoints for the treatment of venous leg ulcers.J Invest Dermatol. 2002; 119: 1420-1425Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar After week 4, it is important to note that the subjects returned to their previous wound care providers and they no longer consistently used limb compression. By report, only three were actively engaged in limb bandage compression therapy. It is very unlikely that an individual with a venous leg ulcer will heal without limb compression. Because of noncompliance with limb compression a natural historic comparison population does not exist. However, the likelihood of similar subjects who used limb compression healing, based on wound size and duration, is about 31% by the 24th week of care.24Margolis 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: 163-168Crossref PubMed Scopus (183) Google Scholar This healing rate is similar to the control arms in randomized clinical trials.22Kantor J Margolis DJ Expected healing rates for chronic wounds.Wounds. 2000; 12: 155-158Google Scholar However, the difference between our results (47% at week 24) and the historical expectation was a risk difference of 16%, which is a number needed to treat ~6 or a relative risk of 1.52 favoring H5.020CMV.PDGF-β. This relative risk is similar to that noted as part of FDA studies where recombinant human PDGF was applied daily for more >12 weeks to treat diabetic foot ulcers.8Falanga V Margolis D Alvarez O Auletta M Maggiacomo F Altman M et al.Rapid healing of venous ulcers and lack of clinical rejection with an allogeneic cultured human skin equivalent. Human Skin Equivalent Investigators Group.Arch Dermatol. 1998; 134: 293-300Crossref PubMed Scopus (579) Google Scholar,25Bartus CL Margolis DJ Reducing the incidence of foot ulceration and amputation in diabetes.Curr Diab Rep. 2004; 4: 413-418Crossref PubMed Scopus (73) Google Scholar,26Falanga V Fujitani RM Diaz C Hunter G Jorizzo J Lawrence PF et al.Systemic treatment of venous leg ulcers with high doses of pentoxifylline: efficacy in a randomized, placebo-controlled trial.Wound Repair Regen. 1997; 7: 208-213Crossref Scopus (101) Google Scholar,27Steed DL Clinical evaluation of recombinant human platelet-derived growth factor for the treatment of lower extremity diabetic ulcers. Diabetic Ulcer Study Group.J Vasc Surg. 1995; 21: 71-78; discussion 79Abstract Full Text Full Text PDF PubMed Scopus (511) Google Scholar Our study may provide evidence that supports the notion that successful vasculogenesis, or de novo formation of new blood vessels from the differentiation of stem cells, requires the interplay of many different cell types including multiple cells that are now classified as endothelial progenitor cells.28Humpert PM Bärtsch U Konrade I Hammes HP Morcos M Kasper M et al.Locally applied mononuclear bone marrow cells restore angiogenesis and promote wound healing in a type 2 diabetic patient.Exp Clin Endocrinol Diabetes. 2005; 113: 538-540Crossref PubMed Scopus (48) Google Scholar,29Vasa M Fichtlscherer S Aicher A Adler K Urbich C Martin H et al.Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease.Circ Res. 2001; 89: E1-E7Crossref PubMed Scopus (2117) Google Scholar,30Lin Y Weisdorf DJ Solovey A Hebbel RP Origins of circulating endothelial cells and endothelial outgrowth from blood.J Clin Invest. 2000; 105: 71-77Crossref PubMed Scopus (1343) Google Scholar In our study, clinically exuberant granulation tissue throughout the wound was noted within the first 2 weeks of injection. The histopathology of biopsy specimens from day 3 wounds transfected by H5.020CMV.PDGF-β demonstrated a statistically significant increase in CD133 cells, a marker of an immature bone marrow–derived endothelial progenitor cell.31Mizrak D Brittan M Alison MR CD133: molecule of the moment.J Pathol. 2008; 214: 3-9Crossref PubMed Scopus (479) Google Scholar While the number of these cells in the wound-edge biopsy increased at day 3, they then decreased at day 28. Interestingly, they also predominated in the sections of the biopsies that represent the site of injections. To the best of our knowledge, this is the first report of PDGF-β application resulting in CD133 migration to wounded tissue. In contrast, the number of blood vessels assessed by positive staining for CD31, which is believed to be a more mature marker for a cell destined to become a mature vascular endothelial cell, did increase at day 28 and the vessels were most prevalent in the subepidermal region of the biopsy. This is probably related to the formation of vessels in healing tissue. Our study was first designed in 1999, at which time we received funding from the National Institute of Arthritis Musculoskeletal and Skin disease to conduct this study. Our investigational new drug application was approved in late 2003 and we published our clinical trial protocol in 2004 (ref. 32Margolis DJ Cromblehome T Herlyn M Cross P Weinberg L Filip J et al.Clinical protocol. Phase I trial to evaluate the safety of H5.020CMV.PDGF-b and limb compression bandage for the treatment of venous leg ulcer: trial A.Hum Gene Ther. 2004; 15: 1003-1019Crossref PubMed Scopus (31) Google Scholar). Because of regulatory concerns about the production of our vector and the safety of conducting gene transfer studies, we were not able to enroll our first study subject until January 2005 and we enrolled our final study subject in summer 2008. This study took nearly 10 years to complet" @default.
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• W2023307607 title "Phase I Study of H5.020CMV.PDGF-β to Treat Venous Leg Ulcer Disease" @default.
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