Theraly Fibrosis' lead candidate, TLY012, selectively targets myofibroblasts
, cells believed to be the critical originators of fibrosis, a condition that affects a range of tissues.
(modified fibroblasts) cause the wound to contract as new tissue is being formed, which pulls the edges of the wound together (Hinz, 2016).
Release of cytokines from stromal myofibroblasts
attracts inflammatory cells and promotes ECM deposition to aid fibroblast migration for tissue remodelling.
The smooth muscle with its characteristic well-defined cytoplasmic borders is replaced by myofibroblasts
(tumor-associated fibroblasts), which have a syncytial growth pattern (Figure 4, A and C).
Fibroblasts control local and distant angiogenesis mediated by bone marrow stem cells; however, they are transformed into invasive types and myofibroblasts
(De Wever & Mareel 2003; Orimo et al., 2005) within the stroma of invasive cancers of the breast, colon, ovaries, pancreas and prostate (Kalluri & Zeisberg, 2006).
The presence of myofibroblasts
and macrophages ([alpha]-SMA, collagen I and CD68, respectively) as well as proliferative activity of the cells within the implant (phosphohistone-3, Anti-H3S10p) was evaluated with immunohistochemical staining of chick embryos.
Alpha-smooth muscle actin cytoskeleton is expressed during wound healing and tissue regeneration and is required for the physiological transition of fibroblasts to myofibroblasts
The exact mechanism of fibroblast transdifferentiation to myofibroblasts
is still unclear.
Highlights from the study observations include:Topically applied remlarsen penetrated into the cornea, without obvious local toxicity following corneal injury; Remlarsen treatment resulted in a decrease in corneal scarring and hazing as assessed by clinical evaluation and histopathology; Remlarsen treatment increased the corneal epithelial thickness, decreased the stromal thickness, and reduced the number of alpha-smooth muscle actin positive myofibroblasts
in the corneal stroma; and Remlarsen treatment resulted in a reduction of pro-fibrotic gene expression from day 7-14 post-injury, indicating that target engagement was achieved in keratocytes and myofibroblasts
in the corneal stroma.
Idiopathic pulmonary fibrosis (IPF) is a severe chronic lung disease with progressive interstitial fibrosis, high mortality, and morbidity occurring mainly in older adults; it is a devastating disease, with poor therapeutic effect and a mean survival time of 2-3 years after diagnosis.,, The hallmark of IPF is the formation of fibroblast foci and the accumulation of extracellular matrix (ECM), resulting in irreversible alteration of pulmonary architecture and ultimately leading to respiratory failure.,, The effector cells in pulmonary fibrosis (PF) are the myofibroblasts
, differentiated fibroblasts, which have contractile properties similar to smooth muscle cells and characterized by the presence of alpha-smooth muscle actin (a-SMA).
Based on the research, that TNF drives the development of myofibroblasts
, the cell type that causes Dupuytren's disease, the research team explored the effects of an anti-TNF drug injected directly into the Dupuytren's nodule tissue.