Update on Pachyonychia Congenita RNAi Trial

Last Friday (20 January, 2008), I was fortunate to attend a talk given by Dr. Kaspar from TransDerm about their Pachyonychia Congenita RNAi program (see 22 January, 2008 Blog). Although the talk covered essentially what is known from publications and previous presentations, there are some details that I think give interesting insights into such an orphan drug development program that underline the potential cost savings through RNAi Therapeutics.

First of all, the phase Ib volume-dose escalation trial involves just one patient with a mutation in a keratin gene that is specifically targeted by the siRNA. If there are no adverse events, then the other five patients in the world with PC known to harbor the same mutation may be given the treatment as well. Although animal genetic data would suggest that knockdown of the wild-type allele should be compensated by the expression of other keratins, the consortium apparently wanted to ensure the highest level of safety by tailoring the treatment to the specific mutation. Which platform technology other than RNAi/gene-based medicines would financially allow for the initiation of a clinical trial for such a minute patient population?

The work at TransDerm leading to the initiation of this clinical study was essentially accomplished by the three employees of this tiny company. This is quite impressive given the scientific and regulatory hurdles one has to overcome to actually enter the clinic. RNAi apparently was helpful in that regard with Dr. Kaspar noting that during his scientific life he had worked with a number of technologies, and well, his experience was a bit mixed. But with RNAi all this has changed. RNAi has exceeded all of his expectations, and judging from his enthusiasm I had every reason to believe him.

Of course, delivery remains an issue, and the talk confirmed that the current trial involves intradermal needle injection of unformulated and unmodified siRNAs. Based on staining results, a lower estimate of the cells that take up the siRNA administered this way is around 20%. This and the fact that the spread of the siRNA is limited to a small area around the injection site in my mind will limit the therapeutic potential of this treatment strategy. Although the observation that such unformulated siRNAs get taken up at all in vivo (but usually not in tissue culture) is very encouraging and should stimulate research into the relevant biological uptake pathways that could lead to advances in RNAi delivery, current conjugation or encapsulation technologies should be able to significantly increase knockdown efficiency following such intradermal injection. As I mentioned before, the company is also working on a lipid-alcohol-based “gene cream” which may also have applications for other tissues. Another promising approach the company is pursuing is the use of 1mm-spaced needle arrays which are sufficiently short so that the tips would not reach the nerves in the skin, thus rendering the treatment painless.

According to Dr. Kaspar, there are 10,000 monogenic congenital diseases, ~20% of which affect the skin. Due to potential cost savings and specificity, RNAi, the poster child of the personalized medicine revolution, is ideally suited to transform the treatment of many of such orphan disorders.