RNAi Clinical Trial Started for Genetic Skin Disorder Pachyonychia Congenita

This week saw the initiation of a clinical trial investigating the use of siRNAs for the treatment of Pachyonychia Congenita (PC). The study is sponsored by the PC Project, a public charity devoted to serving the needs of the ~500 people worldwide affected by this rare genetic disorder, and led by Sancy Leachman from the University of Utah. The siRNA itself, TD101, is the fruit of a collaboration between the International PC Project and the Californian RNAi-focused start-up TransDerm with ties to the shRNA-company SomaGenics.

PC is one of the dominant-negative epithelial fragility disorders caused by the mutation of a keratin gene. There are over 20 keratin genes in the human genome, with two different types forming heterodimers in the assembly of the keratin intermediate filaments which are important for the structural integrity of epithelia such as of the skin. A mutation in one of the dimerization partners may disrupt the organization of the filaments, which in the case of PC results in thickening of nails and skin of the palms and soles. Apart from the obvious cosmetic consequences of the disease, pain due to stress on the palms and soles is a major symptom of the disease for which no specific treatments exist.

Previous studies suggest that a 50% reduction in the mutant protein should get rid of the molecular aggregates caused by the filament assembly defect, and even the total loss of the mutant keratin should be well tolerated due to the expression of compensatory keratins. RNA- and DNA-based treatments offer the best opportunity for a specific treatment as they can address keratins directly and should be able to distinguish between mutant and wild-type genes. After considering a number of technologies, the PC Project has chosen RNAi due to its potential specificity, relative straight-forward mechanism of action which should accelerate drug development.

This is supported by two related publications from the consortia (Hickerson et al. (2007): Single-Nucleotide-Specific siRNA Targeting in a Dominant-Negative Skin Model; Smith et al. (2008): Development of Therapeutic siRNAs for Pachyonychia Congenita) which demonstrate the ability of siRNAs to specifically down-regulate the mutant keratin with an almost complete reversal of the aggregation phenotype. This is shown in both in vitro tissue culture and in vivo mouse footpad models involving the use of keratin-reporter genes.

While these studies provide proof-of-concept of RNAi for the treatment of PC, the in vivo studies were limited to the knockdown of reporter genes co-transfected with the siRNAs, rather than targeting endogenous genes in the skin epithelium. It is difficult to judge from such studies the overall delivery efficiency since cells that take up the reporter gene are likely to take up the siRNA as well, even when most of the remaining cells have not taken up any of the siRNA. (note: similar reservations apply to the recently initiated phase I RNAi studies for HBV by Nucleonics which are also heavily based on co-transfection experiments.)

The mouse models involved intradermally injected, unmodified siRNAs in a simple PBS buffer. While TransDerm is working on a topical lipid-based “gene crème”, it appears that at least for the phase Ib studies the siRNAs, targeting one of the more common mutations in PC, will be intradermally delivered by needle injection. One concern here is whether the area that such a delivery method can reach is sufficient to alleviate the symptoms of PC. Another is that using unmodified siRNAs in PBS over stabilized formulations will unnecessarily sacrifice some of the efficacy as well as necessitate more frequent treatment. Clearly, there is room for improvement, but the phase Ib studies should provide precious clinical data and inform future treatment strategies.

In addition to more sophisticated delivery methods and formulations, such strategies could also involve DNA-directed RNAi where autologous skin transplants and/or stem cells of the skin are stably corrected ex vivo, e.g. by lentiviral transduction of shRNAs, and then reapplied to the patient. This may be preferable to repeat needle injections.

TransDerm hopes that providing proof-of-concept for an RNAi Therapeutic of such a rare skin disorder with little commercial potential will be a stepping-stone for addressing much larger patient populations. This illustrates once more the value of proof-of-concept studies in general for RNAi since the ability of deliver one RNAi treatment could be rapidly expanded to delivering many more RNAi Therapeutics for the same tissue.

It will be interesting to see whether TransDerm, which by the way has opted for a classical Tuschl siRNA rather than a synthetic shRNA like SomaGenics is using, will be successful not only in the clinic, but also in their corporate strategy. In the absence of any RNAi core IP, the development of RNAi delivery technologies for the skin is probably their best shot in creating shareholder value.

PS: I wonder what happened to Sirna Therapeutics’ dermatology program which in their first development program aimed for siRNA-mediated permanent hair removal. The prospect of RNAi dermatology products is certainly exciting, especially if it were possible to develop convenient delivery methods such as topical cremes.