Enhancement of the Beneficial Effects of Mesenchymal Stem Cell (MSC) Treatment by the Caveolin-1 Scaffolding Domain Peptide (CSD)

Abstract
Systemic sclerosissclerodermaSScis a chronic connective tissue disease in which lung fibrosis is the most
frequent cause of deathSSc and idiopathic pulmonary fibrosis are the two most common disease that falls
under the interstitial lung diseasesILDa grouping of devastating diseases in which lung fibrosis leads to
progressive shortness of breatha very poor quality of lifeand death within a few yearsAutologous local Mesenchymal Stem CellMSCinjections have been shown to have a short term beneficial
effect on SSc patients by healing ulcersreturning feeling to the fingersand enhancing facial skin elasticity and
the ability to open and close the mouthIn contrastbeneficial effects of MSC therapy on lung fibrosis have not
been reportedCaveolinis a promising therapeutic target in fibrotic diseasesThe effects of caveolindeficiency in cells and
in animals can be reversed using the CaveolinScaffolding Domain PeptideCSDWe have shown that many
cell types from SSc patientsfibroblastsmonocytesMSCsare deficient in caveolinleading to collagen
overexpression by fibroblastshypermigration by monocytesand myofibroblast differentiation at the expense of
adipocyte differentiation by MSCsWe have shown analogous effects in a mouse model in vivoCSD has
beneficial effects on lung and skin fibrosis including reversing the thinning of the subcutaneous fat layerthis
thinning is also observed in SSc patientsRecentlywe have shown that the beneficial effects of MSCs and full length CSD on lung fibrosis are synergistic
and thatsubdomains of CSD are as effective as full length CSD in various in vitro and in vivo assayBased on
these studieswe willAimIdentify a subdomain of CSDlead compoundwith the same activity as full lengthamino acid CSD in synergizing with MSC therapy in having a beneficial effect on lung fibrosisAimDevelop
stabilitysolubilityand pharmacokinetic data for each candidate subdomain to determine if any of these peptides
has significant advantages over the othersThese studies will help predict a human dose level and the safety
margin we will have in human studiesIn summarythe improvements in MSC therapy that will result from the completion of this project will have great
commercial potential because of their ability to enhance the quality of life and lifespan of SSc patients Narrative
Systemic sclerosisSScis a chronic connective tissue disease in which lung fibrosis is the most frequent cause
of deathOur long term objective is to develop an optimal version of the CaveolinScaffolding Domain PeptideCSDthatin combination with the injection of Mesenchymal Stem CellMSCsstops the progression of SSc
lung disease