Darvadstrocel

Perianal fistula is a common manifestation of Crohn’s disease. It typically presents as fissures penetrating the intestinal lumen and perianal skin surface and is accompanied by local inflammation, which bacterial infections and fecal contamination can exacerbate. At the site of inflammation, there is increased infiltration of lymphocytes, increased release of inflammatory cytokines (e.g., interleukin (IL)-6, TNF-α, IL12), and upregulated matrix metalloproteinase (MMP) enzymes.

The pathogenesis of perianal fistulas is unclear; however, there is evidence of epithelial-to-mesenchymal transition (EMT) involvement, among other proposed mechanisms like altered immune response due to genetic predisposition and overexpression of matrix remodelling enzymes. EMT is a biologic process by which the epithelial characteristics of a cell are reprogrammed to adopt mesenchymal phenotype. Cells with a mesenchymal phenotype have increased invasion and metastasis potential. EMT is characterized by increased expression of MMPs, MMP-induced degradation of the extracellular matrix, and the loss of cell polarity and invasive ability. Although EMT is a normal physiological response to restore intestinal barrier after epithelial damage, immunomediators such as TGF-β and IL-13 can aberrantly upregulate EMT so that it becomes a detrimental process.

Darvadstrocel contains expanded human allogeneic adipose-derived mesenchymal stem cells. Its main mode of therapeutic action comes from its immunomodulatory and anti-inflammatory effects, rather than an ability to stimulate tissue regeneration. Upon direct injection into the site of tissue injury, inflammatory cytokines released by activated immune cells - such as IFN-γ - activate darvadstrocel, or expanded adipose stem cells. Darvadstrocel suppresses T cell activation and proliferation; dendritic cell differentiation, maturation, and function; B-cell differentiation; and natural killer cell (NKC) proliferation. By reducing pro-inflammatory cytokine secretion by dendritic cells and NKCs, darvadstrocel induces a more anti-inflammatory microenvironment. Darvadstrocel also enhances the production of IL-10 and transforming growth factor-β, which are cytokines that promote Treg differentiation and inhibit Th1 cell differentiation.