Monday, April 30, 2007
Due to reasons discussed in the previous post, almost all of these programs are Direct RNAi programs, i.e. the siRNA is administered close to the diseased site. All except for Acuity's program are also with siRNAs that have been chemically modified (to enhance stability etc), and it remains to be seen whether Acuity's strategy to plunge into the clinic first was a wise one. Sirna Therapeutics soon followed suit, but I think took the right decision to invest time to carefully think about how to position their potential product in the more and more crowded AMD market. Sirna Therapeutics was also the first public company based on RNAi. Formerly known as Ribozyme Pharmaceuticals, they leveraged their experience with RNAs to build an operation that had all the tools to to build a decent IP portfolio and quickly enter the clinic. This IP portfolio is mostly based on chemistry and targeting many genes one by one such that it could claim exclusivity for targeting those genes with RNAi. It remains to be seen, however, how this brute force approach will hold up in the patent courts. Also, ISIS pharmaceuticals may contest some of their chemistry claims. However, the strategy has paid off extremely well at least for those that engineered it with Merck's takeover of the company last year for about 50x the price it had been valued before it committed to RNAi. SR Pharma, known as of today as "Silence Therapeutics", of the UK, looks as if it was seting itself up for a similar sale with an almost 8-fold price appreciation since last year.
The brightest star in the sky of RNAi Therapeutics by far, however, is Alnylam Pharmaceuticals. This is the company whose scientific founders were seminal in the development of RNAi and microRNAs, particularly in humans. Consequently, the company sits on an unparalled exclusive IP portfolio that gives them freedom to operate and pursue highly lucrative deals with Big Pharma and Biotech. These deals should help it through the development phase and have brought in already well over $100M. All this is managed by a seasoned team, led by CEO John Maraganore, that has considerable experience in developing succesful biotech companies (many of them hail from Biogen). It is also the company mentioned by the Karolinska Institute in their explanation for the 2006 Nobel Prize Award to Fire and Mello, as having demonstrated the therapeutic potential of RNAi through ground-breaking studies. These studies represent important de-risking events that continue to attract academic and indrustrial collaborators and important investments, including the RNAi Therapeutics field as a whole.
Other notable companies involved in RNAi Therapeutics include Benitec, a pure-play Australian company that uses DNA-based RNAi vectors to tackle a range of viral diseases, Nastech Pharmaceuticals (not a pure-play; focuses on siRNA delivery and Dicer-substrate technology), and large pharmaceuticals such as Merck, Novartis, GSK, and Pfizer, and probably many more knocking on the doors of Alnylam and co.
Sunday, April 29, 2007
The efficient delivery of the RNAi agent is frequently cited as the main hurdle to the wide application of RNAi. While local delivery such as needle injection into the eye for ocular diseases or inhalation for lung-related conditions has a relatively high likelihood of success, systemic delivery, e.g. needed to reach metastatic cancer cells hidden in the body, is a taller order. However, a number of delivery methods are being tested, some borrowed from older oligonucleotide-based technologies like liposomes, some more innovative. It is likely that no one-fits-all solution will emerge, but strategies that are tailored to the specific disease. Particularly interesting are approaches where a synthetic siRNA is coupled to agents such as monoclonal antibodies or RNA aptamers which can selectively target cells. Hence, the specificity of the siRNA is compounded by the specificity of its delivery. This should also help in reducing the likelihood of potentially harmful off-target effects.
Off-targeting, the suppression of non-targeted genes is mainly a consequence of the siRNA acting like a microRNA. MicroRNAs are related endogenous 20-24 nucleotide small RNAs that recognise their targets through less than perfect complementarity. Although this typically does not downregulate target genes as dramatically as an efficient siRNA might do, nobody can be sure that a 2-3 fold reduction in a “random” gene will not have adverse side-effects. I should stress that this specificity is probably still much better than many other drug-classes today, but we would like to do better, especially when human health and the substantial resources needed for the development of a drug are at stake. Helped by the knowledge of the human genome, bioninformatics already can winnow down the number of potential off-targets, thus reducing the likelihood of an adverse side-effect. More lately, however, and as demonstrated by the work of Dharmacon scientists, it has become possible to modify the siRNA such that it will lose much of its microRNA abilities while retaining potent RNAi-like cleavage potential. I view this as a particular exciting development.
Chemical modification of siRNAs can also help to enhance its drug-like properties such as half-life, metabolism etc. However, it was only quite recently shown quite by Alnylam Pharmaceuticals, viewed by many as the leading RNAi Therapeutics company, that siRNAs may knock down genes with a profile that may allow dosing every 2 to 4 weeks. This is a great relief and opens up RNAi for many more, particularly chronic applications such as hypercholesterolemia, than would have been the case if the knockdown was limited up to 4 days after administration. The latter is typically observed with cultured cancer cell lines and is due to dilution of the siRNAs following frequent cell divisions. For some genetic diseases, viral gene therapy vectors for the expression of hairpin RNAs that are processed to siRNAs by the endogenous RNAi machinery are a further important option. They should allow for the more long-term expression of RNAi effector molecules, although the risk-benefit equation is shifted for DNA-based therapies.
In summary, many strategies are being explored to develop RNAi as a safe and efficient therapy. While human trials for each siRNA will have to be performed to evaluate its specific therapeutic value, as the risk of RNAi Therapeutics gets more manageable each day, it promises to become one of the most specific and versatile drug class to date.
Saturday, April 28, 2007
For those who want to understand more about the basic mechanism and discovery of RNAi, a popular documentary can be found at PBS Nova: http://www.pbs.org/wgbh/nova/sciencenow/3210/02.html
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