Plea to Sarepta and Arrowhead: Just Focus on Aberrant Exon 1 Transcript in Huntington’s Disease

Last week, uniQure achieved a breakthrough in developing disease-modifying therapies for Huntington’s Disease by showing that AMT-130 slowed disease progression by 75%.  AMT-130 is a DNA-directed RNAi construct targeting a sequence in the triplett-expanded exon 1 of the 67 exons-containing huntingtin gene.  Since other approaches aimed at lowering full-length huntingtin, but leaving exon 1 mRNA untouched have fallen short (e.g. tominersen by Ionis and Roche) this is very strong support that targeting the aberrant exon 1 transcript is essential for success.

The aberrant exon 1 transcript, and likely the protein produced from that, is loaded with polyglutamine-encoding CAG tripletts, has been shown in animal studies to be exceptionally toxic and is also produced in patients (see previous blog entry 'Huntington's Disease Therapeutics Finally Breaking Through!'), the amount of which is correlated with triplett expansion size based on comments by uniQure CMO Walid Abi-Saab at a conference earlier this year).  Add to this the observation that a phase 3 trial with tominersen had to be stopped due to the oligo performing worse thancontrol, maybe it is time for a radically new idea:

accept that the old notion of Huntington’s Disease being an autosomal dominant disease caused by toxic full-length triplett-expanded huntingtin has been wrong, and full-length huntingtin indeed is an important protein to have. Instead, leave full-length huntingtin alone and exclusively target the aberrant exon 1 ‘fragment’.   Hey, have you ever considered the possibility that the polyQ htt protein aggregates are not cleavage products from full-length Htt?  Why always so complicated?  Why consider both exon 1 and full-length Htt contributing meaningfully to disease?  Should the properties of a short protein largely made up of polyglutamine be radically different from that of a much larger one containing the same polyglutamine stretch?

Sarepta and Arrowhead have shared plans to enter the clinic with a systemically administered RNAi conjugate for Huntington’s Disease.  A systemically administered option would be a very valuable one since, especially in light of the one-time administered AMT-130, repeat intrathecal administration is less attractive.   The Tfr1-targeted ARO-HTT being prepared for clinical trial application this year apparently does not affect exon 1 transcript.  The excuse given is that it is difficult to find an effective RNAi trigger in the merely 102 nucleotide exon 1 target space.

The good news: by focusing exlusively on aberrant exon 1 transcript, 7000+ nucleotides of additional target space (from 5’ end of intron 1) opens up.  

What good is it to have a trigger that is great at knocking down a transcript when it is aimed at the wrong target?  It is not too late and can be explained to the market.