Hello everybody,
I am new at this tech talk. I enjoy to see other people putting together science and investment. My perception of ISIS is the following. Antisense makes sense: whether as inserts or as modified short nucleotides. If the concept succeeds, it will be with ISIS. These guys are good scientists and the CEO is a MD who worked for drug companies before. First, I was doubting about the concept. Oligonucleotides (modified or not) are expensive to produce. Then how are the target cells specifically...targetted? (All cell types absorb to some degree DNA floating around in liposomes). In vitro, no problems, it is sufficient to add oligos to the cell medium. High concentrations of oligos are achieved, cells in culture gobble it up and bingo you see the effect. In vivo, in the patients or in animals, this is another story. If you inject oligos intravenously, they are widely distributed throughout the whole body fluids. How to achieve the high local concentrations necessary for your target cells to absorb it? Macrophages (the cells that clean the blood) in the spleen and in lymph nodes will first swallow your molecule. People at ISIS and in other companies are working at addressing this problem by placing ligands at the liposomes surface (liposomes are convenient little bags where you place your DNA). Ligands are recognized by the receptors present at the surface of the cell that is targeted (and hopefully the surface of this cell only). Nothing original there. What really struck me is that Dr Crook, the ISIS CEO, is medically oriented (that sounds funny for a biotech company, but when you think about it, most biotech are run either by PhD with no medical background or by MBA, also without medical background). The whole antisense concept had been demonstrated unambiguously in vitro (with cell culture) and for viral infections (where the gene(s) causing cells to die are well defined).
In vivo, the antisense concept remained to be supported. So at ISIS, they thought about targeting diseases 1) where high local concentrations of antisense oligos can be easily achieved (to reproduce in vitro conditions), maybe a natural cavity, where antisense would persist, at high concentrations and 2) whose etiology is a virus, since it had been demonstrated in vitro...
regardless of chemical modifications, or the economic importance of the disease.
So what a more relevant organ/disease than the eye (a retinitis due to a virus (CMV)), which can be injected with high concentrations of oligos which can remain there pretty intact, and where viral replication is pretty well localized.
Personally I think that a viral arthritis would be the next logical choice (one can easily inject a joint). Unfortunately, there is not a lot of this around (but ISIS also targets mRNAs of important inflammatory cytokines).
Of course, these thoughts imply that it will be much harder to devise efficient antisense oligos (or polynucleotides) for the treatment of systemic diseases.
Anyway all that to say that it is not so much the antisense concept that distinguishes ISIS from other antisense companies but rather the astute strategy they use to get there.
Best regards
Daniel |
