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And here is more, which I certainly don't fully understand, but I do think I learned something about how the body responds to the treatment. This statement seems to say that the effects on fibrosis are the side-effect of a side-effect of the direct-effect of the treatment. That is, drug inhibits X, which leads to a condition Y, which the body responds to with Z, which has anti-fibrotic effect.

Halofuginone exerts its effects by acting as a high affinity inhibitor of the enzyme Glutamyl-Prolyl tRNA synthetase. Inhibition of prolyl tRNA charging leads to the accumulation of uncharged prolyl tRNAs, which serve as a signal to initiate the amino acid starvation response, which in turn exerts anti-inflammatory and anti-fibrotic effects. [5]

 

http://en.wikipedia.org/wiki/Halofuginone

 

 

Hi,

Here is an excerpt from this article which explained a lot to me:

Mechanisms of muscle weakness in muscular dystrophy

http://jgp.rupress.org/content/136/1/29.full

Muscle from DMD patients is known to express increased levels of TGF-β, and protein can be localized within the extracellular matrix (Bernasconi et al., 1995). TGF-β drives the synthesis of collagen and promotes the growth and differentiation of fibroblasts. It was proposed that in muscular dystrophy, myocyte necrosis or injury leads to TGF-β signaling, which promotes fibrosis at the expense of regeneration by satellite cells. TGF-β1 is capable of converting myoblast cells into myofibroblasts, raising the possibility that satellite cells are activated but differentiate into noncontractile tissue (Li et al., 2004). Phosphorylated SMAD2/3, an indication of TGF-β signaling, is present in mdx muscle fibers (Cohn et al., 2007). Antibodies that inactivate TGF-β or the angiotensin II receptor blocker losartan, which indirectly decreases TGF-β secretion, reduced SMAD signaling and decreased the severity of the mdx phenotype, including improved grip strength (Cohn et al., 2007).

Dystrophic muscle has a substantial mononuclear cell infiltrate that includes macrophages, lymphocytes, neutrophils, and eosinophils. The role of these immune cells is increasingly being considered in the pathogenesis of muscular dystrophy. For example, these cells are a likely source of proteases responsible for LTBP4 cleavage and subsequent TGF-β activation. Recently, Vetrone et al. (2009) identified a subset of T cells specifically associated with dystrophic skeletal muscle. These cells display T cell receptors with the Vβ8.1/8.2 rearrangement and express the extracellular matrix phosphoprotein, osteopontin. Deletion of osteopontin had several positive effects in the mdx mouse. Neutrophil invasion into the muscle was significantly reduced, and the number of immune-suppressing T lymphocytes, T regulatory cells, was increased. Overall, deleting osteopontin decreased TGF-β and fibrosis, and it increased grip strength in the mdx mouse. A more balanced view of the immune system, including T regulatory cells, is required in muscular dystrophy and is the subject of ongoing investigation.

So they are skippping the healthy volunteer phase and testing it directly in DMD boys?

David said:

And here is more, which I certainly don't fully understand, but I do think I learned something about how the body responds to the treatment. This statement seems to say that the effects on fibrosis are the side-effect of a side-effect of the direct-effect of the treatment. That is, drug inhibits X, which leads to a condition Y, which the body responds to with Z, which has anti-fibrotic effect.

Halofuginone exerts its effects by acting as a high affinity inhibitor of the enzyme Glutamyl-Prolyl tRNA synthetase. Inhibition of prolyl tRNA charging leads to the accumulation of uncharged prolyl tRNAs, which serve as a signal to initiate the amino acid starvation response, which in turn exerts anti-inflammatory and anti-fibrotic effects. [5]

 

http://en.wikipedia.org/wiki/Halofuginone

 

 

Interesting that bisphosphonates also inhibit osteopontin?

Eileen - many thanks. Most of your post is over my head but I do now appreciate the connection to immune system.

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