RNAi Also Conquers the Central Nervous System

In the span of a day, RNAi Therapeutics have gone from a mechanism widely viewed as being constrained to the liver only, to a major therapeutic modality for many targets and indications in a variety of tissues.  Due to the demonstrations in the liver, lung (yesterday), and today the central nervous system to potently and specifically knock down genes with infrequent dosing, RNAi will play a prominent role in today’s precision medicine-oriented drug development.

Employing C16 lipid-conjugated, chemically stabilized RNAi triggers, Alnylam and their partner in CNS drug development Regeneron achieved 84-90% maximal target gene knockdown with knockdown persisting at >70% for at least 3 months after a single dose.

Since chemical stability has been key to the successes in the lung, CNS, and also liver, it seems very likely that similar breakthroughs will be achievable for muscle, kidney, adipose tissues, and (in the words of Alnylam's President) 'even tumors' that Alnylam and Arrowhead are working on.

The initial target in the phase I study of ALN-APP was amyloid beta precursor protein (APP). Unlike the armada of antibodies that have targeted every known aggregation form of abeta for the treatment of Alzheimer’s, ALN-APP reduces them all and before they are even made thereby offering a unique angle to this important target.  An even more exciting near-term application of ALN-APP in my opinion is for cerebral amyloid angiopathy (CAA) where abeta accumulation near blood vessels can lead to intracerebral hemorrhage.  Studies with antibodies in Alzheimer’s have actually led to fatal damage to those very intracerebral blood vessels by causing local inflammation, and thereby make them a bad choice for CAA.

Beyond abeta and tau for Alzheimer’s, the CNS in particular abounds with otherwise difficult-to-drug important targets for diseases like Parkinson’s, Huntington’s, ALS, spinocerebellar ataxias for which RNAi is ideally suited.

The prolonged and robust knockdown observed is significantly better than what has been observed for previous RNaseH antisense candidates such as against SOD1 and tau (~50% target gene lowerings).  Safety also appears to be superior to the broadly phosphorothioated antisense molecules with no changes in neuronal markers of damage and inflammation seen with ALN-APP compared to placebo.

The US FDA though slapped a clinical hold on the multi-dose part of the trial based on findings in standard preclinical animal tox studies at doses well above what will be needed in the clinic.  The single dose exploration study, however, has been allowed to continue, and Canada has already allowed the multi-dose part to go ahead.  It therefore seems highly unlikely that the findings could derail ALN-APP or even this technology approach at this point.

With the recent news, the pharmaceutical landscape has changed and Big Pharmaceutical companies will have to think hard whether not having a stake in RNAi as a platform is viable.  The achievement is also one of delivery and stabilization chemistry which can be more broadly applied to other oligonucleotide therapeutics modalities in the CNS.

Looking Ahead: Alnylam-Medtronic Alliance Stop-Go Decision Expected Soon

In early 2005, Alnylam and Medtronic announced a joint product development program to evaluate the use of Medtronic’s implantable drug delivery devices for RNAi Therapeutics applications of the central nervous system (CNS). If at the end of this development program a joint decision for the continuation of this program were made, Medtronic would take an equity position in Alnylam and additional investments following the achievement of certain milestones.

According to regulatory filings, the original decision making due date was April 2007, but was then postponed to July 2007. It is interesting to speculate that this delay may have been either caused by scientific uncertainties or is the consequence of drafting a comprehensive and therefore complicated co-operation agreement. Certainly, in development time-frames, 3 months do not seem to be sufficient to reasonably expect major new breakthroughs had there been fundamental scientific problems.

Medtronic realised early on the potential of RNAi as a new class of drugs that could be used with their drug delivery devices. Only shortly before the 2005 agreement, in August 2004, Medtronic published a patent on the treatment of neurodegenerative diseases such as Parkinson’s, Alzheimer’s, and Huntington’s, through intracranially delivered siRNAs using Medtronic’s implantable catheters (United States Patent 20040162255). Two years later, a similar patent was published for the treatment of neuropathic pain.

While pertinent in vivo data are lacking in these patents, it is clear that Alnylam already has amply tested Medtronic’s devices. Josephine Lai from the University of Arizona Health Sciences Center in Tucson, a Alnylam collaborator, for example has published strong in vivo data on intrathecally delivered siRNAs [Luo et al. Mol. Pain 1: 29 (2005)]. It is also of note that in this study, siRNAs were most efficient when formulated in the liposomal i-Fect transfection reagent from Neuromics. The same reagent was also successfully applied in rescuing mice from lethal flavivirus infection of the CNS [Kumar et al. Plos Med. 3: e96 (2006)].

One potential limitation with the local delivery of siRNAs and shRNA vectors such as AAV, however, is to achieve sufficient diffusion of the RNAi inducing agent to its target cells. That diffusion of macromolecules in the dense matrix of the CNS may also be an issue with a device from Medtronic similar to the one Alnylam is evaluating, is suggested by the failure of a phase II clinical experience of the neurotrophic factor GDNF for Parkinson’s [Salvatore et al. Exp. Neurol. 202:497 (2006)]. This particular experience, however, has to be taken with a grain of salt, as there appears to be some controversy about the interpretation of the trial results [Slevin et al. Annals Neurol. 59:989 (2006)]. A positive announcement on the Medtronic-Alnylam alliance may therefore indicate that it is possible to achieve sufficient siRNA diffusion.

Nevertheless, local delivery may not be sufficient for diseases where the whole brain has to be targeted, such as in viral infections and brain tumours. Here, systemic delivery solutions are needed. While the blood-brain barrier has historically been regarded as a major obstacle to achieving that goal, targeted approaches such as the rabies-peptide conjugation approach that I have highlighted in my June 19 Blog (“New Breakthrough in the Systemic Delivery of RNAi for the Brain”) and similar efforts make me hopeful that a range of both local and systemic delivery strategies will eventually prove successful in addressing a number of diseases of unmet medical need. These issues also highlight once more, that it will be critical to carefully tailor the delivery of an RNAi Therapeutic to its disease application.

Blog Watch: The ‘Old Vic’ blog talks about a possible takeover or significant RNAi Therapeutics alliance involving Silence Therapeutics: http://www.sharescity.com/2007/07/silence-therapeutics-takeover-rumours.html