Wayne, I keep referring to the 'DrugBaron' article about...

Wayne,

I keep referring to the 'DrugBaron' article about Sarepta's dismal GT data reveal in January - pure GOLD.

Clearly the additional "Dystrophin" is not all that - there are other factors at play at a cellular level.

Both Pfizer and Sarepta are now admitting this - and both will need to find a solution if they are to save their $$$ Billion dollar investment in DMD.

How do they deal with "cell mediated inflammation" ???

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....To summarise, DMD is a particularly bad choice for gene therapy because we already know that low expression of the gene product causes only a very mild impairment of muscle function (observed in very young children).  The progressive nature of the disease is caused by the phenotypic response to that initial weakness.

Even at a molecular level, the biological mechanism of this response is relatively-well understood.  Strain in the muscle tissue drives expression of TGFb1 (the canonical member of the TGF-beta superfamily), a cytokine that drives a co-ordinated expression of intracellular and extracellular muscle proteins, including the major contractile proteins, actin and myosin, and the key extracellular components collagen and fibronectin.  These increase the contractile capacity of the muscle, and in the healthy individual yield the familiar increase in muscle bulk (hypertrophy) that we observe with regular exercise (and exactly the reverse that occurs after long periods of inactivity, such as bed rest during illness).

But if the muscle has a genetic defect that reduces tractive effort for a given amount of contractile apparatus (something we also see in Hypertrophic Cardiomyopathies, where a genetic mutation in cardiac myosin very mildly reduces contractile function, exactly as with the dystrophin mutation in DMD), then higher levels of TGF-beta are needed to achieve a given level of function.  And over time something bad happens.
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