Peter-
A couple of thoughts regarding your post.
First, I would like to see some preclinical efficacy data for Ranolazine in animal "migraine" models" like the one that M. Moskowitz at Harvard has established. My view is that model is predictable for human efficacy. The question regarding this neuronal circuit is to what extent the relevant Na+ channels are expressed in the spinal trigeminal nerve and the spinal trigeminal nucleus (as well as the thalamic relay neuronal system). I would be worried about the potency of the compound, as I mentioned in the post to Rick regarding the abstract. Do you know to what extent R gets crosses the blood-brain barrier?
I do view the TTX resistant sodium channels as interesting chronic pain targets, but the challenges have been good high-throughput assays, Na+ channel selectivity, and compound potency. MRK has made some progress here based upon some presentations and discussions with some of their scientists.
As tuck mentioned, VRTX got their pain program from the Aurora munch. A couple of years ago I rec'd a call from a head hunter looking for suggestions for a VP of neuroscience at the San Diego VRTX site. They wanted a channel expert who understood pain mechanisms and CNS in general. I do not know whether they hired such a person. I think Josh Boger worked out a deal (? with GSK) for pain mechanisms, but I have not seen much if anything publicly reported.
As one final point, there is some very interesting human genetics work on congenital insensitivity to pain involving the 1.7 Na+ channel, but you are likely aware of this. Two relevant abstracts are shown below:
An SCN9A channelopathy causes congenital inability to experience pain.Cox JJ, Reimann F, Nicholas AK, Thornton G, Roberts E, Springell K, Karbani G, Jafri H, Mannan J, Raashid Y, Al-Gazali L, Hamamy H, Valente EM, Gorman S, Williams R, McHale DP, Wood JN, Gribble FM, Woods CG.
Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome/MRC Building, Addenbrooke's Hospital, Cambridge CB2 0XY, UK.
The complete inability to sense pain in an otherwise healthy individual is a very rare phenotype. In three consanguineous families from northern Pakistan, we mapped the condition as an autosomal-recessive trait to chromosome 2q24.3. This region contains the gene SCN9A, encoding the alpha-subunit of the voltage-gated sodium channel, Na(v)1.7, which is strongly expressed in nociceptive neurons. Sequence analysis of SCN9A in affected individuals revealed three distinct homozygous nonsense mutations (S459X, I767X and W897X). We show that these mutations cause loss of function of Na(v)1.7 by co-expression of wild-type or mutant human Na(v)1.7 with sodium channel beta(1) and beta(2) subunits in HEK293 cells. In cells expressing mutant Na(v)1.7, the currents were no greater than background. Our data suggest that SCN9A is an essential and non-redundant requirement for nociception in humans. These findings should stimulate the search for novel analgesics that selectively target this sodium channel subunit.
SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes.
Fertleman CR, Baker MD, Parker KA, Moffatt S, Elmslie FV, Abrahamsen B, Ostman J, Klugbauer N, Wood JN, Gardiner RM, Rees M.
Department of Paediatrics and Child Health, Royal Free and University College Medical School, University College London, 5 University Street, London WC1E 6JJ, United Kingdom.
Paroxysmal extreme pain disorder (PEPD), previously known as familial rectal pain (FRP, or OMIM 167400), is an inherited condition characterized by paroxysms of rectal, ocular, or submandibular pain with flushing. A genome-wide linkage search followed by mutational analysis of the candidate gene SCN9A, which encodes hNa(v)1.7, identified eight missense mutations in 11 families and 2 sporadic cases. Functional analysis in vitro of three of these mutant Na(v)1.7 channels revealed a reduction in fast inactivation, leading to persistent sodium current. Other mutations in SCN9A associated with more negative activation thresholds are known to cause primary erythermalgia (PE). Carbamazepine, a drug that is effective in PEPD, but not PE, showed selective block of persistent current associated with PEPD mutants, but did not affect the negative activation threshold of a PE mutant. PEPD and PE are allelic variants with distinct underlying biophysical mechanisms and represent a separate class of peripheral neuronal sodium channelopathy.
BJ |
