We recently shared the news with you that the Genentech/Roche clinical trial of the huntingtin-lowering drug RG6042 is coming to NZ. For information on the NZ arm of the trial head over to our news section. Here we explain the science behind the drug RG6042.
Huntington’s disease is caused by a specific mutation (called a repeat expansion) in the Huntingtin gene. This mutation leads to the production of a ‘faulty’ Huntingtin protein causing brain cells to become dysfunctional and/or die. In order to try to treat HD we need to stop that faulty protein from being made by the cell. So, we go back a step to the gene – the recipe for the protein.
RG6042 is an Antisense Oligonucleotide (ASOs). The image below shows the basic process of ASO gene silencing; but before we walk through that process, let’s make a stop in at genetics101. DNA is made up of bases, there are 4 types of bases (A, T, C, and G). The bases work in pairs; A teams up with T, and C teams up with G. These base pairs are what holds the 2 strands of DNA together. DNA doesn’t do its own stunts, it makes something called messenger RNA, and sends that off to make protein. Messenger RNA is usually single stranded, and has the same string of bases as its DNA counterpart, except that T becomes U. The messenger RNA usually gets ‘read’ by special cellular machinery that decodes the string of bases to get the recipe for the protein the DNA wants to make.
In the case of Huntington’s disease, the message from the DNA has been tampered with, so we don’t want that message to get out. This is where the ASOs come in. The ASO is made to have a ‘matching’ string of bases to the messenger RNA, meaning that where the messenger RNA has a C, the ASO has a G – the C and G team up, as do all the other base pairs, and the ASO sticks to the messenger RNA. The ASO being stuck to the messenger RNA means that it can’t have its (incorrect) message read, therefore no faulty protein can be made.
ASO - Antisense Oligonucleotide - small pieces of DNA or RNA that can stick to RNA and stop the message getting out (i.e. stop translation)
Bases - DNA bases, base pairs - A ‘unit’ of DNA, the bases are like the words in an instruction manual, and when read all together you get the ‘instructions for life’
DNA - Deoxyribonucleic acid - Our genes, holds the recipes for proteins, has two strands
Genentech - Biotechnology company
Protein - molecules that make up the structure and function of all cells in our bodies
Roche - Pharmaceutical company, parent company to Genentech
RNA - Ribonucleic acid - A copy of DNA, has only one strand, sends DNAs message to other parts of the cell
mRNA - messenger RNA -
Transcription - the first step in the process of gene expression, when the DNA is copied into RNA
Translation - the second step in the process of gene expression, when the RNA message is read and a protein is made
Currently, the RG6042 drug has passed preliminary scientific testing and is now into rigorous clinical testing. The clinical tests are divided into phases. Below is a summary of the different phases of clinical testing which any new drug needs to undergo to be licenced for use on patients as a treatment :
• Pre-clinical: testing the drug/intervention in animal models of the disease – show that it is safe and effective
• Phase 1: Tested on a small group of healthy volunteers. Testing safety in humans and tolerated dose range
• Phase 2: Drug tested in patients. Further safety and efficacy trials. Determine best dose and regimen for Phase 3. Ideal outcome: drug may be safe and effective in small number of patients
• Note: sometimes the Phase 1 and Phase 2 trials are combined – like in the case of HTTrx, the first trial in humans was a Phase1/2 trial.
• Phase 3: Test drug in larger group of patients. Often worldwide. Goal – confirm evidence from Phase 2 that drug may be safe and effective. With large number of patients, can assess frequency and severity of side effects. More data about benefits, dose, regimen. Data from Phase 3 used to apply for approval to release the drug to the market.
• To Patients/Phase 4: continued safety and efficacy monitoring when the drug is on the market and being used more widely (assess long term risks and rare side effects).