Darvadstrocel 30million cells/6ml dispersion for injection vials

Perianal fistula is a common manifestation of Crohn’s disease.[A244524] 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.[L39759] 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.[A244524][L39759]

The pathogenesis of perianal fistulas is unclear; however, there is evidence of epithelial-to-mesenchymal transition (EMT) involvement,[A244534] among other proposed mechanisms like altered immune response due to genetic predisposition [A244524] and overexpression of matrix remodelling enzymes.[A244529] 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.[A244539] 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.[A244529]

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.[A244529] 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.[L39759] 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 T_reg differentiation and inhibit Th1 cell differentiation.[A244524][A244529]