KECORT Study: An International e-Delphi Study on the Treatment of KEloids Using Intralesional CORTicosteroids in Clinical Practice.

BACKGROUND: Intralesional corticosteroid administration (ICA) is a first-line keloid treatment. However, it faces significant variability in current clinical and scientific practice, which hinders comparability of treatment results. OBJECTIVES: The aim of the study was to reach consensus on different aspects of ICA using hypodermic needles in keloids among an international group of dermatologists and plastic surgeons specialized in keloid treatment to provide consensus-based clinical treatment recommendations for all physicians treating keloids. METHODS: The keloid expert panel of 12 dermatologists and 11 plastic surgeons rated 30 statements. Two online e-Delphi rounds were held, both with a response rate of 100%. Fifteen (65%) keloid experts participated in the final consensus meetings. Consensus was defined as ≥ 75% of the participants choosing agree or strongly agree on a 7-point Likert scale. RESULTS: Consensus was reached on treatment goals, indication for ICA, triamcinolone acetonide (TAC) 40 mg/mL as the preferred corticosteroid administered at a maximum of 80 mg per month and at intervals of 4 weeks, minimizing pain during ICA, the use of 1 mL syringes and 25 or 27 Gauge needles, blanching as endpoint of successful infiltration, caution of not injecting subcutaneously, and the option of making multiple passes in very firm keloids prior to infiltration. Consensus could not be reached on TAC dosing, methods of prior local anesthesia, and location of injection. CONCLUSIONS: This e-Delphi study provides important clinical treatment recommendations on essential aspects of ICA in keloids. By implementing these recommendations, uniformity of ICA in keloid treatment will increase and better treatment results may be achieved.

Skin fibrosis is accompanied by increased expression of secreted frizzled-related protein-2.

Dermal fibrosis is a consequence of damage to skin and is accompanied by dysfunction and cosmetic disfigurement. Improved understanding of the pathological factors driving skin fibrosis is critical to development of therapeutic modalities. Here, we describe that the Wnt signalling antagonist SFRP2 is upregulated in organotypic keratinocyte cultures upon experimental reduced hydration, a model that simulates the aberrant epidermal barrier state characteristic of several skin pathologies, including those that manifest in development of fibrosis. Consistent with this, we find that SFRP2 is overexpressed in both the dermis and epidermis of human hypertrophic scar tissue and lesional tissue of a mouse scleroderma model. Knockdown of SFRP2 expression in human fibroblasts antagonises proliferation and myofibroblast differentiation, including deposition of type I collagen, suggesting that SFRP2 signalling in fibroblasts may contribute to propagation of fibrosis in hypertrophic scar, as well as in other clinical indications characterised by skin fibrosis.

Anti-fibrotic effects of statin drugs: A review of evidence and mechanisms.

Fibrosis is a pathological repair process common among organs, that responds to tissue damage by replacement with non-functional connective tissue. Despite the widespread prevalence of tissue fibrosis, manifesting in numerous disease states across myriad organs, therapeutic modalities to prevent or alleviate fibrosis are severely lacking in quantity and efficacy. Alongside development of new drugs, repurposing of existing drugs may be a complementary strategy to elect anti-fibrotic compounds for pharmacologic treatment of tissue fibrosis. Drug repurposing can provide key advantages to de novo drug discovery, harnessing the benefits of previously elucidated mechanisms of action and already existing pharmacokinetic profiles. One class of drugs with a wealth of clinical data and extensively studied safety profiles is the statins, a class of antilipidemic drugs widely prescribed for hypercholesterolemia. In addition to these widely utilized lipid-lowering effects, increasing data from cellular, pre-clinical mammalian, and clinical human studies have also demonstrated that statins are able to alleviate tissue fibrosis originating from a variety of pathological insults via lesser-studied, pleiotropic effects of these drugs. Here we review literature demonstrating evidence for direct effects of statins antagonistic to fibrosis, as well as much of the available mechanistic data underlying these effects. A more complete understanding of the anti-fibrotic effects of statins may paint a clearer picture of their anti-fibrotic potential for various clinical indications. Additionally, more lucid comprehension of the mechanisms by which statins exert anti-fibrotic effects may aid in development of novel therapeutic agents that target similar pathways but with greater specificity or efficacy.

Comment on "Scar-Degrading Endothelial Cells as a Treatment for Advanced Liver Fibrosis".

Cellular therapies show promise for treatment of fibrosis. A recent article presents a strategy and proof-of-concept for delivering stimulated cells to degrade hepatic collagen in vivo. A discussion is presented surrounding the strengths of this approach and the potential to generalize this strategy of optimizing cell sources and activation stimuli to treat other types of fibrosis.

Epidermal Potentiation of Dermal Fibrosis: Lessons from Occlusion and Mucosal Healing.

Fibrotic skin conditions, such as hypertrophic and keloid scars, frequently result from injury to the skin and as sequelae to surgical procedures. The development of skin fibrosis may lead to patient discomfort, limitation in range of motion, and cosmetic disfigurement. Despite the frequency of skin fibrosis, treatments that seek to address the root causes of fibrosis are lacking. Much research into fibrotic pathophysiology has focused on dermal pathology, but less research has been performed to understand aberrations in fibrotic epidermis, leading to an incomplete understanding of dermal fibrosis. Herein, literature on occlusion, a treatment modality known to reduce dermal fibrosis, in part through accelerating wound healing and regulating aberrant epidermal inflammation that otherwise drives fibrosis in the dermis, is reviewed. The review focuses on epidermal-dermal crosstalk, which contributes to the development and maintenance of dermal fibrosis, an underemphasized interplay that may yield novel strategies for treatment if understood in more detail.

Prediction and Demonstration of Retinoic Acid Receptor Agonist Ch55 as an Antifibrotic Agent in the Dermis.

The prevalence of fibrotic diseases and the lack of pharmacologic modalities to effectively treat them impart particular importance to the discovery of novel antifibrotic therapies. The repurposing of drugs with existing mechanisms of action and/or clinical data is a promising approach for the treatment of fibrotic diseases. One paradigm that pervades all fibrotic diseases is the pathological myofibroblast, a collagen-secreting, contractile mesenchymal cell that is responsible for the deposition of fibrotic tissue. In this study, we use a gene expression paradigm characteristic of activated myofibroblasts in combination with the Connectivity Map to select compounds that are predicted to reverse the pathological gene expression signature associated with the myofibroblast and thus contain the potential for use as antifibrotic compounds. We tested a small list of these compounds in a first-pass screen, applying them to fibroblasts, and identified the retinoic acid receptor agonist Ch55 as a potential hit. Further investigation exhibited and elucidated the antifibrotic effects of Ch55 in vitro as well as showing antiscarring activity upon intradermal application in a preclinical rabbit ear hypertrophic scar model. We hope that similar predictions to uncover antiscarring compounds may yield further preclinical and ultimately clinical success.

Amnion membranes support wound granulation in a delayed murine excisional wound model.

Chronic or delayed healing wounds constitute an ever-increasing burden on healthcare providers and patients alike. Thus, therapeutic modalities that are tailored to particular deficiencies in the delayed wound healing response are of critical importance to improve clinical outcomes. Human amnion-derived viable and devitalized allografts have demonstrated clinical efficacy in promoting the closure of delayed healing wounds, but the mechanisms responsible for this efficacy and the specific wound healing processes modulated by these tissues are not fully understood. Here, we utilized a diabetic murine excisional wound model in which healing is driven by granulation and re-epithelialization, and we applied viable (vHAMA) or devitalized (dHAMA) amnion-derived allografts to the wound bed in order to determine their effects on wound healing processes. Compared to control wounds that were allowed to heal in the absence of treatment, wounds to which vHAMA or dHAMA were applied demonstrated enhanced deposition of granulation tissue accompanied by increased cellular proliferation and increased de novo angiogenesis, while vHAMA-treated wounds also demonstrated accelerated re-epithelialization. Taken together, these data suggest that both vHAMA and dHAMA facilitate wound healing through promoting processes critical to granulation tissue formation. Further understanding of the cellular and tissue mechanisms underlying the effects of tissue-derived matrices on wound healing will enable tailored prescription of their use in order to maximize clinical benefit.

Comparison of Thermal Burn-Induced and Excisional-Induced Scarring in Animal Models: A Review of the Literature.

Significance: Scar formation is a natural result of mammalian wound healing. In humans and other mammals, however, deep dermal wounds and thermal injuries often result in formation of hypertrophic scars, leading to substantial morbidity and lending great importance to development of therapeutic modalities for burn scars. Clinical Issues: Thus, preclinical burn wound models that adequately simulate processes underlying human burn-induced wound healing, particularly those processes leading to chronic inflammation and development of hypertrophic scars, are critical to developing further treatment paradigms for clinical use. Approach: In this study, we review literature describing various burn models, focusing on their characteristics and the functional readouts that lead to generation of useful data. We also briefly discuss recent work using human ex vivo skin culture as an alternative to animal models, as well as our own development of rabbit ear wound models for burn scars, and assess the pros and cons of these models compared to other models. Future Direction: Understanding of the strengths and weaknesses of preclinical burn wound models will enable choice of the most appropriate wound model to answer particular clinically relevant questions, furthering research aimed at treating burn scars.

Rethinking Upper Blepharoplasty: The Impact of Pretarsal Show.

BACKGROUND: Conventional upper blepharoplasty relies on skin, muscle, and fat excision to restore ideal pretarsal space-to-upper lid fold ratios. The purpose of this study was to identify presenting topographic features of upper blepharoplasty patients and their effect on cosmetic outcomes. METHODS: This is a retrospective review of patients who underwent upper blepharoplasty at the authors' institution from 1997 to 2017. Preoperative and postoperative photographs were standardized using Adobe Illustrator to an iris diameter of 11.5 mm. Pretarsal and upper lid fold heights were measured at five locations. Patients were classified into three groups based on preoperative pretarsal show: none, partial, or complete. Photographs were randomized in PowerPoint and given a cosmetic score of 0 to 5 by four independent reviewers. RESULTS: Three hundred sixteen patients were included, 42 men (13 percent) and 274 women (87 percent). Group 1 included 101 eyes (16 percent), group 2 had 159 eyes (25 percent), and group 3 had 372 eyes (59 percent). Mean cosmetic score increased from 1.75 to 2.38 postoperatively (p < 0.001), with a significantly lower improvement in scores in group 3 compared to groups 2 and 1 for both sexes (p < 0.01). For group 3, those with midpupil pretarsal heights greater than 4 mm had a significantly lower postoperative aesthetic score (1.95) compared with those less than or equal to 4 mm (2.50) (p < 0.001). CONCLUSIONS: Many patients presenting for upper blepharoplasty have complete pretarsal show and are at risk for worse cosmetic outcomes using conventional skin excision techniques. Adjunctive procedures such as fat grafting and ptosis repair should be considered in this group. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.

Allogeneic Decellularized Muscle Scaffold Is Less Fibrogenic and Inflammatory than Acellular Dermal Matrices in a Rat Model of Skeletal Muscle Regeneration.

BACKGROUND: Skeletal muscle trauma can produce grave functional deficits, but therapeutic options remain limited. The authors studied whether a decellularized skeletal muscle scaffold would provide benefits in inducing skeletal muscle regeneration over acellular dermal matrices. METHODS: Eighty-two rat muscle defects were surgically created and assigned to no intervention or implantation of AlloDerm, Strattice, decellularized rat muscle, or decellularized rat dermis to 30 or 60 days. Decellularized rat muscle and dermis were prepared using a negative pressure-assisted protocol. Assessment for cellularity, neovascularization, myogenesis, inflammation and fibrosis were done histologically and by polymerase chain reaction. RESULTS: Histology showed relative hypercellularity of AlloDerm (p < 0.003); Strattice appeared encapsulated. Immunofluorescence for CD31 and myosin heavy chain in decellularized rat muscle revealed dense microvasculature and peripheral islands of myogenesis. MyoD expression in muscle scaffolds was 23-fold higher than in controls (p < 0.01). Decellularized rat muscle showed no up-regulation of COX-2 (p < 0.05), with less expression than decellularized rat dermis and Strattice (p < 0.002). Decellularized rat muscle scaffolds expressed tumor necrosis factor-α less than Strattice, AlloDerm, and decellularized rat dermis (p < 0.01); collagen-1a less than decellularized rat dermis and Strattice (p < 0.04); α-smooth muscle actin 7-fold less than AlloDerm (p = 0.04); and connective tissue growth factor less than Strattice, AlloDerm, and decellularized rat dermis (p < 0.02). CONCLUSION: Decellularized muscle matrix appears to reduce inflammation and fibrosis in an animal muscle defect as compared with dermal matrices and promotes greater expression of myocyte differentiation-inducing genes.

Invited Discussion On: Efficacy and Safety of Intralesional Triamcinolone Versus Combination of Triamcinolone with 5-Fluorouracil in the Treatment of Keloids and Hypertrophic Scars: A Systematic Review and Meta-Analysis.

Level of Evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Liposome-encapsulated statins reduce hypertrophic scarring through topical application.

Hypertrophic scar is an important clinical problem with limited therapeutic options. Aside from their roles as 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, statins have also been demonstrated to decrease scarring by reducing connective tissue growth factor (CTGF) expression. However, poor penetrative ability limits their utility as topical treatments for hypertrophic scar. Here, we aim to develop novel statin formulations using liposomes to enhance dermal penetrative ability and to evaluate their efficacy against formation of hypertrophic scar utilizing our validated rabbit ear hypertrophic scar model. Liposomal simvastatin or pravastatin were compounded using a novel, flexible liposomal formulation and applied topically to rabbit ear hypertrophic scars daily from postoperation day (POD) 14 until POD 25. Scar color, including erythema and melanin, was measured using reflectance spectrophotometry on POD 28, and scar tissue was harvested for evaluation of scar elevation index as well as gene and protein expression. Human foreskin fibroblasts were also treated with statin formulations and CCN2 expression was determined by quantitative PCR. Both simvastatin and pravastatin were efficiently encapsulated in liposomes, forming nanometer-scale particles possessing highly negative charges. Topical treatment with liposomal simvastatin and pravastatin at 6.5% concentration significantly reduced scar elevation index and decreased type I/III collagen content and myofibroblast persistence in the wound. The erythema/vascularity of scars was reduced by liposomal statin treatment, with concomitant decrease of CD31 expression as measured histologically. Expression levels of transcripts encoding CTGF, collagen I, and collagen III collagen in scar tissue were also decreased by liposomal pravastatin treatment, as were myofibroblast persistence and the type I/III collagen ratio as assessed by immunofluorescence and picrosirus red staining, respectively. Treatment of human foreskin fibroblasts with simvastatin or with liposome-encapsulated pravastatin resulted in decreased expression of transcript encoding CTGF. Overall, our novel statin formulations encapsulated in liposomes were successfully delivered through topical application, significantly reducing hypertrophic scarring in a rabbit ear model.

Decellularized Fetal Matrix Suppresses Fibrotic Gene Expression and Promotes Myogenesis in a Rat Model of Volumetric Muscle Loss.

BACKGROUND: Traumatic muscle loss often results in poor functional restoration. Skeletal muscle injuries cannot be repaired without substantial fibrosis and loss of muscle function. Given its regenerative properties, the authors evaluated outcomes of fetal tissue-derived decellularized matrix for skeletal muscle regeneration. The authors hypothesized that fetal matrix would lead to enhanced myogenesis and suppress inflammation and fibrosis. METHODS: Composite tissue composed of dermis, subcutaneous tissue, and panniculus carnosus was harvested from the trunk of New Zealand White rabbit fetuses on gestational day 24 and from Sprague-Dawley rats on gestational day 18 and neonatal day 3, and decellularized using a sodium dodecyl sulfate-based negative-pressure protocol. Six, 10-mm-diameter, full-thickness rat latissimus dorsi wounds were created for each treatment, matrix was implanted (excluding the defect groups), and the wounds were allowed to heal for 60 days. Analyses were performed to characterize myogenesis, neovascularization, inflammation, and fibrosis at harvest. RESULTS: Significant myocyte ingrowth was visualized in both allogeneic and xenogeneic fetal matrix groups compared to neonatal and defect groups based on myosin heavy chain immunofluorescence staining. Microvascular networks were appreciated within all implanted matrices. At day 60, expression of Ccn2, Col1a1, and Ptgs2 were decreased in fetal matrix groups compared to defect. Neonatal matrix-implanted wounds failed to show decreased expression of Col1a1 or Ptgs2, and demonstrated increased expression of Tnf, but also demonstrated a significant reduction in Ccn2 expression. CONCLUSIONS: Initial studies of fetal matrices demonstrate promise for muscle regeneration in a rat latissimus dorsi model. Further research is necessary to evaluate fetal matrix for future translational use and better understand its effects.

The sodium channel NaX : Possible player in excitation-contraction coupling.

The sodium channel NaX (encoded by the SCN7A gene) was originally identified in the heart and skeletal muscle and is structurally similar to the other voltage-gated sodium channels but does not appear to be voltage gated. Although NaX is expressed at high levels in cardiac and skeletal muscle, little information exists on the function of NaX in these tissues. Transcriptional profiling of ion channels in the heart in a subset of patients with Brugada syndrome revealed an inverse relationship between the expression of NaX and NaV 1.5 suggesting that, in cardiac myocytes, the expression of these channels may be linked. We propose that NaX plays a role in excitation-contraction coupling based on our experimental observations. Here we show that in cardiac myocytes, NaX is expressed in a striated pattern on the sarcolemma in regions corresponding to the sarcomeric M-line. Knocking down NaX expression decreased NaV 1.5 mRNA and protein and reduced the inward sodium current (INa+ ) following cell depolarization. When the expression of NaV 1.5 was knocked down, ~85% of the INa+ was reduced consistent with the observations that NaV 1.5 is the main voltage-gated sodium channel in cardiac muscle and that NaX likely does not directly participate in mediating the INa+ following depolarization. Silencing NaV 1.5 expression led to significant upregulation of NaX mRNA. Similar to NaV 1.5, NaX protein levels were rapidly downregulated when the intracellular [Ca2+ ] was increased either by CaCl2 or caffeine. These data suggest that a relationship exists between NaX and NaV 1.5 and that NaX may play a role in excitation-contraction coupling.

Knockdown of sodium channel Nax reduces dermatitis symptoms in rabbit skin.

The skin plays a critical role in maintenance of water homeostasis. Dysfunction of the skin barrier causes not only delayed wound healing and hypertrophic scarring, but it also contributes to the development of various skin diseases. Dermatitis is a chronic inflammatory skin disorder that has several different subtypes. Skin of contact dermatitis and atopic dermatitis (AD) show epidermal barrier dysfunction. Nax is a sodium channel that regulates inflammatory gene expression in response to perturbation of barrier function of the skin. We found that in vivo knockdown of Nax using RNAi reduced hyperkeratosis and keratinocyte hyperproliferation in rabbit ear dermatitic skin. Increased infiltration of inflammatory cells (mast cells, eosinophils, T cells, and macrophages), a characteristic of dermatitis, was reduced by Nax knockdown. Upregulation of PAR-2 and thymic stromal lymphopoietin (TSLP), which induce Th2-mediated allergic responses, was inhibited by Nax knockdown. In addition, expression of COX-2, IL-1ß, IL-8, and S100A9, which are downstream genes of Nax and are involved in dermatitis pathogenesis, were also decreased by Nax knockdown. Our data show that knockdown of Nax relieved dermatitis symptoms in vivo and indicate that Nax is a novel therapeutic target for dermatitis, which currently has limited therapeutic options.

Simplified Lateral Brow Lift under Local Anesthesia for Correction of Lateral Hooding.

BACKGROUND: A limited incision lateral brow lift has been described as an alternative to the endoscopic or the bicoronal approaches. The senior author has developed a safe and effective lateral brow lift technique that can be performed in an office setting under local anesthesia. METHODS: We retrospectively reviewed 150 consecutive patients who underwent a brow lift by the senior author (TAM). The technique begins with an upper blepharoplasty incision which is used to divide the corrugator under direct vision, followed by a release of the periorbital retaining ligaments. The lateral temporal incision is the access point for dissection above the deep temporal fascia then connecting to the subperiosteal plane, allowing full mobility of the brow. Galea is advanced with sutures and redundant skin is excised. RESULTS: All patients treated with this technique had resolution of lateral brow hooding. Two temporary neuropraxias of the frontal branch of the facial nerve were observed with full resolution and no permanent nerve injuries occurred. The revision rate was 7% and there was a 3% incidence of delayed wound healing at the temporal incision with no infections. One hundred forty-two patients (97%) underwent this procedure with sedation, 52 of which (35%) were in the office with light oral sedation. CONCLUSIONS: The limited incision lateral brow lift as described allows for safe elevation of the lateral brow. When complemented by upper blepharoplasty, this technique provides excellent and natural-appearing rejuvenation of the upper face.

In vivo stress relaxation of human scalp.

OBJECTIVE: Conduct a first in vivo study on the large deformation stress relaxation behavior of the human scalp. METHODS: This study was conducted during Mohs micrographic surgery of the scalp of 14 patients aged 59-90 with wounds initially ranging from 9 to 41 mm wide. The initial wound diameter was measured under zero applied force. Then, the force required to close each wound using a single size 1 nylon suture and a SUTUREGARD suture retention device was measured, after which the suture was then locked in the retention device at fixed displacement. At time points of 300 s, 600 s, and 1800 s, the suture retention device was released, and the wound opening was again recorded at zero force, and the force required to close the wound was recorded. RESULTS: The average wound closure force relaxed by 44% and 65% after 300 s and 1800 s, respectively. Average wound width decreased 30% and 42%, after 300 s and 1800 s, respectively, due to creep deformation. Furthermore, all wounds relaxed to be below 15 N of closure force after 600 s, which is considered the maximum clinically acceptable force. A relaxation time of ∼270 s and a threshold force for creep of ∼5 N was found. SIGNIFICANCE: Results of this study provide the first quantitative clinical guidance for efficient scalp closure of large wounds by creep deformation and stress relaxation. Furthermore, the methodology developed here can be used as a basis for future in vivo studies of the stress relaxation and creep deformation of human scalp, which in turn can provide data for the development and validation of constitutive models for scalp deformation.

Imiquimod-induced skin inflammation is relieved by knockdown of sodium channel Nax.

Nax is an atypical sodium channel that mediates inflammatory pathways in pathological conditions of the skin. In this study, we developed a skin inflammation model in the rabbit ear through application of imiquimod (IMQ). Knockdown of Nax using RNAi attenuated IMQ-induced skin inflammation, including skin erythema, scaling and papule formation. Histologic analysis showed that thickening and insufficient differentiation of the epidermis found in psoriasis-like skin were normalized by administration of Nax -RNAi. Excessive infiltration of inflammatory cells found in inflammatory lesions, such as mast cells, eosinophils, neutrophils, T cells and macrophages, was reduced by Nax -RNAi. Expression of S100A9, which is a downstream gene of Nax and a mediator of inflammation, was decreased by Nax -RNAi. Our results demonstrated that knockdown of Nax ameliorated IMQ-induced psoriasis-like skin inflammation in vivo. Thus, targeting of Nax may represent a potential therapeutic option for the treatment of psoriasis.

Volumetric Changes of the Mid and Lower Face with Animation and the Standardization of Three-Dimensional Facial Imaging.

BACKGROUND: The objective of this study was to quantify volumetric changes of the mid and lower face caused by facial expression to understand how procedural results measured by three-dimensional imaging can be influenced by lack of standardization. Secondarily, the study identified soft-tissue surface landmarks that can be used to ensure the standardization of three-dimensional images. METHODS: Three-dimensional facial images of subjects performing 22 facial expressions or changes in head position were captured. Variable degrees of animation during smiling and frowning were also evaluated. Volumetric changes of the malar and jowl regions were quantified using a three-dimensional superimposed image subtraction technique. The translation of 14 standard soft-tissue surface landmarks was assessed during various facial animations to determine which three-dimensional landmarks can be used to standardize three-dimensional images. RESULTS: Twenty subjects participated in the study. Sixteen of the 22 facial expression studies had a significant effect on malar and/or jowl volume. Significant volume changes were noted with subtle animation during smiling and frowning. A combination of five landmarks (i.e., glabella, bilateral cheilion, pogonion, and laryngeal prominence) can be used to standardize three-dimensional images for evaluation of mid and lower facial volume changes. CONCLUSIONS: Subtle facial expressions may cause significant volumetric changes in the mid and lower face that can mimic the desired outcomes of surgical and nonsurgical facial rejuvenation procedures. The five-point referencing system allows one to identify subtle changes in head position and facial expression and may aid in the standardization of three-dimensional images.

A MicroRNA-29 Mimic (Remlarsen) Represses Extracellular Matrix Expression and Fibroplasia in the Skin.

MicroRNA-29 (miR-29) negatively regulates fibrosis and is downregulated in multiple fibrotic organs and tissues, including in the skin. miR-29 mimics prevent pulmonary fibrosis in mouse models but have not previously been tested in the skin. This study aimed to identify pharmacodynamic biomarkers of miR-29 in mouse skin, to translate those biomarkers across multiple species, and to assess the pharmacodynamic activity of a miR-29b mimic (remlarsen) in a clinical trial. miR-29 biomarkers were selected based on gene function and mRNA expression using quantitative reverse transcriptase polymerase chain reaction. Those biomarkers comprised multiple collagens and other miR-29 direct and indirect targets and were conserved across species; remlarsen regulated their expression in mouse, rat, and rabbit skin wounds and in human skin fibroblasts in culture, while a miR-29 inhibitor reciprocally regulated their expression. Biomarker expression translated to clinical proof-of-mechanism; in a double-blinded, placebo-randomized, within-subject controlled clinical trial of single and multiple ascending doses of remlarsen in normal healthy volunteers, remlarsen repressed collagen expression and the development of fibroplasia in incisional skin wounds. These results suggest that remlarsen may be an effective therapeutic to prevent formation of a fibrotic scar (hypertrophic scar or keloid) or to prevent cutaneous fibrosis, such as scleroderma.