Re: CLDN
I've harped on about this one on twitter, likely to the point of boring readers.
I've worked hands-on with AAV (serotype 9), and I know from first hand experience that the doses CLDN is using in humans are high doses for a rat. These doses are insufficient for a dog heart, let alone a human heart. Dosing does matter, since these AAV are replication defective, so dosing needs to scale with heart size.
Second point is that intracoronary bloodstream administration is not effective in large animals. In the dog, intracoronary does not work whereas in the rat it is highly effective and cardiotropic. Some of it has to do with the tissue tropism of the virus. However, we found that if the virus isn't directly injected into the myocardium, you see no expression. At the near placebo doses that CLDN uses, their wishful delivery method will assure very little transduction.
Their papers also do a very poor job of convincing that large animal models show actual expression. In fact, one of the papers using pigs shows that SERCA protein expression does not increase following AAV administration.
That's just a weak structure upon which to build a clinical program.
