Complex 3-Dimensional in vitro Human Skin Tissue Models for Scleroderma

PROJECT SUMMARY Sclerodermasystemic sclerosisSScis an autoimmune disease of unknown etiology that is characterized by vascular dysfunctionfibrosisand inflammationOne in three patients dies withinyears of diagnosisgiving SSc the highest case fatality rate of any systemic autoimmune diseaseA lack of biologically relevant SSc disease models has created a critical unmet need for more efficient preclinical drug screening models that can provide fastermore cost effective ways of predicting the success or failure of drugs designed to treat SScRecent advances in tissue engineering have resulted inD skin tissue based disease models that can closely mimic SSc in humansThis advancement will shorten the preclinical drug development timelinesave animal livesincrease drug success ratesand inform FDA decision making for the development of new and effective disease therapeuticsIn phase I SBIR workthe Celdara Medical research team developedD skin like tissue models that accurately recapitulate the SSc phenotype and are an important advancement over the currently available monolayerD tissue culturesPhase II work is now proposed to develop this into a commercialpreclinical drug screening platformnamed SclerExBy developingD skin models at Celdarathis promising in vitro system can now be paired with Celdara s existing portfolio of SSc diagnostics and SScfibrosisand cancer drug development effortsIt can also be provided to Celdara s pharma partners for pre clinical drug testing of anti fibrotic compounds that exist in their development pipelinesThis work will leverage SclerEx skin like models for drug screeningwhich will advance complex tissue models for other organ systemssuch as lung and esophagusBy using multiplepatient derived cell types to optimizeD tissues to establish robustSSc specificD tissue models that can serve as preclinical drug screening platforms for new therapeutic agents for SScthis project will advance the identification of anti fibrotic therapiesThe aims of the work proposed are toevaluate the reproducibility of the previously optimizedD tissue model for SSc by performing assay validation and consistent benchmark measures that are reproducible and reliabledemonstrate and evaluate the utility of the model for drug screening by performing proof of concept screening using known SSc therapies and therapies currently in clinical trialsandidentify and control for the circulating factor sin plasma sera that result in increased skin thickness and or impact monocyte differentiation by Luminex assays or high throughput protein screeningso it will generate a highly reproducibleD tissue model system PROJECT NARRATIVE The goal of this proposal is to evaluateD bioengineeredskin like tissue models that mimic systemic sclerosisSSca platform that we have named SclerEx to fill a need for preclinical drug testing in a physiologically relevant systemThe development of robustpredictiveand cost effective skin models for SSc will improve the ability to test and identify the drugs most likely to be effective in SSc patientsthereby providing a vast improvement for preclinical drug developmentThe systems will also provide a platform for personalized medicine in SScfor which no equivalent currently exists