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.