Liftoff: First humans treated with gene silencing drugs for HD!

Originally published on HD Buzz on October 19, 2015 (By Dr Jeff Carroll on October 22, 2015, Edited by Dr Tamara Maiuri )

Today brings news that the first Huntington’s Disease patients have been successfully dosed with gene silencing drugs targeting the HD gene. These brave volunteers are the first HD patients to ever be treated with drugs designed to attack HD at its root cause, a treatment approach with huge potential. What about this news has us so excited?

Gene Silencing

Many HD researchers, including the editors of HDBuzz, believe that a treatment approach called gene silencing is the most exciting thing happening in HD research right now. To understand why, we need to cover a little bit of HD basics.

Gene silencing drugs interfere with the way that genes are used to make damaging proteins. ASOs work by targeting specific messenger molecules for destruction, which has the effect of reducing levels of the damaging protein.

Gene silencing drugs interfere with the way that genes are used to make damaging proteins. ASOs work by targeting specific messenger molecules for destruction, which has the effect of reducing levels of the damaging protein.

Every HD patient has inherited a mutated version of a gene that we sometimes call the HD gene. In scientific circles, the gene is actually called Huntingtin, and abbreviated HTT, but that can be a bit confusing.

Everyone on earth has two copies of the HD gene, one they inherited from mom and one from dad. In every HD patient, one of these copies has a sort of genetic stutter, a repetitive bit of code near one end of the gene that tweaks the way this gene does its job. This turns out to be bad news – Huntington’s Disease is the consequence of this stutter lengthening beyond a critical threshold.

We still don’t understand a lot about HD. What the HD gene normally does, why does it have this repetitive stretch of DNA, and what makes it stretch out are questions that we still don’t have scientific consensus on.

But what’s clear beyond a shadow of a doubt is that every single HD patient has the same type of mutation – a lengthening of the repetitive stretch of DNA in the HD gene. In the code scientists use to describe genetic sequences, the stuttering letters are abbreviated “C-A-G”, which is why you might have heard of people talking about “C-A-G repeats”.

This genetic certainty is terrifying for family members – if your mom or dad has HD you have an exactly 50% chance of inheriting this awful mutation. But there’s a flip side to this bad news, which is that this certainty gives us a really good target for trying to attack HD. Since every single HD patient has a mutant HD gene, why don’t we just try to get rid of the mutant gene itself?

In previous generations, this would have been like asking someone to reach up into the sky and pluck out your favorite star, but we live in amazing times. It turns out that this kind of thing might actually be possible now because over the last 20-30 years, techniques have been developed by scientists that let us pretty much switch off a given gene at will.

At root, scientists are a curious bunch. As they’ve poked and prodded how cells achieve particular tasks, they’ve uncovered a wide range of ways to shut off certain genes. You might hear about “antisense oligonucleotides (ASOs)”, or “zinc finger nucleases (ZFNs)” or even “transcription activator-like effector nucleases (TALENs)”. The idea behind this zoo of approaches is the same: trick cells into shutting off the HD gene and only the HD gene.

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