A road less traveled: how making less huntingtin can alter somatic instability and may delay symptoms

One mystery that many scientists think holds the key to curing HD is its mysterious age of onset. Although people with HD carry the expanded gene from birth, they generally don’t develop symptoms until later in life, suggesting something bad is brewing beneath the surface! One explanation, which has gained significant traction in recent years, is a process called somatic instabilitysomatic expansion A process in which the CAG repeat in the Huntingtin gene can change over a person’s lifetime in some cells of the body, particularly in the brain., where the expansion worsens over a person’s life. Recent work from the lab of Dr. Jeff Carroll at the University of Washington investigated several genetic techniques to understand what causes somatic instabilitysomatic expansion A process in which the CAG repeat in the Huntingtin gene can change over a person’s lifetime in some cells of the body, particularly in the brain. and whether huntingtin-lowering therapeuticstherapeutics treatments might slow it down. 

An Unstable Repeat

To understand somatic instabilitysomatic expansion A process in which the CAG repeat in the Huntingtin gene can change over a person’s lifetime in some cells of the body, particularly in the brain., let’s briefly revisit how genes work. Normally, genes like huntingtin, or HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15, are copied to make messenger molecules, called mRNAmessenger RNA A message molecule, based on DNA, used by cells as the final set of instructions for making a protein., through a process known as transcriptiontranscription the first step in making a protein from the recipe stored in a gene. Transcription means making a working copy of the gene from RNA, a chemical messenger similar to DNA.. These genetic messages can then be used as a template to make proteins through another process called translation. 

However, in HD, the HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 gene contains extra genetic letters (C-A-Gs) that repeat too many times, causing its mRNAmessenger RNA A message molecule, based on DNA, used by cells as the final set of instructions for making a protein. message to create an abnormal protein. In some cells, these repeating CAGs can grow even longer over someone’s life, leading to mRNAmessenger RNA A message molecule, based on DNA, used by cells as the final set of instructions for making a protein. that is increasingly repetitive. By the time symptoms appear, these CAG repeats may have grown into the hundreds in certain cells. The continuously expanding CAG repeatCAG repeat The stretch of DNA at the beginning of the HD gene, which contains the sequence CAG repeated many times, and is abnormally long in people who will develop HD in HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15, called somatic instabilitysomatic expansion A process in which the CAG repeat in the Huntingtin gene can change over a person’s lifetime in some cells of the body, particularly in the brain., is a leading theory for why the onset of HD is typically delayed into adulthood. 

Many ongoing clinical trials are focused on reducing the amount of HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 produced from the faulty gene. However, it’s unclear if lowering HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 levels will slow down the growth of the CAG repeatCAG repeat The stretch of DNA at the beginning of the HD gene, which contains the sequence CAG repeated many times, and is abnormally long in people who will develop HD in the HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 gene. Although somatic instabilitysomatic expansion A process in which the CAG repeat in the Huntingtin gene can change over a person’s lifetime in some cells of the body, particularly in the brain. is a prime suspect for causing HD’s delayed onset, it’s still only a correlation. Regardless, it’s certainly worth investigating what causes it and whether HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15-lowering therapies, which are already in clinical trials, can affect it. 

Dialling Down Huntingtin 

In a new study, a team at the University of Washington tested whether HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 lowering affects somatic instabilitysomatic expansion A process in which the CAG repeat in the Huntingtin gene can change over a person’s lifetime in some cells of the body, particularly in the brain.. From previous work, they had used a type of therapy called Antisense OligonucleotidesASOs A type of gene silencing treatment in which specially designed DNA molecules are used to switch off a gene (ASOsASOs A type of gene silencing treatment in which specially designed DNA molecules are used to switch off a gene), which bind mRNAmessenger RNA A message molecule, based on DNA, used by cells as the final set of instructions for making a protein. and send it to the cell’s trash can, to lower HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 levels in mice. They followed up on these experiments and discovered that ASOsASOs A type of gene silencing treatment in which specially designed DNA molecules are used to switch off a gene also reduced CAG repeatCAG repeat The stretch of DNA at the beginning of the HD gene, which contains the sequence CAG repeated many times, and is abnormally long in people who will develop HD growth by about 50%. This is good news because several ongoing clinical trials are already investigating ASOsASOs A type of gene silencing treatment in which specially designed DNA molecules are used to switch off a gene.

Although the ability of ASOsASOs A type of gene silencing treatment in which specially designed DNA molecules are used to switch off a gene to reduce target mRNAmessenger RNA A message molecule, based on DNA, used by cells as the final set of instructions for making a protein. levels is well understood, the researchers were surprised that it stunted the growth of CAGs in the HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 gene. They suspected the ASOsASOs A type of gene silencing treatment in which specially designed DNA molecules are used to switch off a gene might also disrupt mRNAmessenger RNA A message molecule, based on DNA, used by cells as the final set of instructions for making a protein. at its source – a process called transcriptiontranscription the first step in making a protein from the recipe stored in a gene. Transcription means making a working copy of the gene from RNA, a chemical messenger similar to DNA.. Recent work by other groups has linked rates of transcriptiontranscription the first step in making a protein from the recipe stored in a gene. Transcription means making a working copy of the gene from RNA, a chemical messenger similar to DNA. with the growth of CAGs, such that the more the HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 gene is used to make mRNAmessenger RNA A message molecule, based on DNA, used by cells as the final set of instructions for making a protein., the quicker the CAGs build up. This hypothesis led the team to investigate exactly how ASOsASOs A type of gene silencing treatment in which specially designed DNA molecules are used to switch off a gene were slowing CAG growth. 

The researchers considered two possible ways ASOsASOs A type of gene silencing treatment in which specially designed DNA molecules are used to switch off a gene might be slowing somatic instabilitysomatic expansion A process in which the CAG repeat in the Huntingtin gene can change over a person’s lifetime in some cells of the body, particularly in the brain.. 

1. The HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 protein itself was responsible for somatic instabilitysomatic expansion A process in which the CAG repeat in the Huntingtin gene can change over a person’s lifetime in some cells of the body, particularly in the brain., and by reducing the production of HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15, ASOsASOs A type of gene silencing treatment in which specially designed DNA molecules are used to switch off a gene reduced somatic instabilitysomatic expansion A process in which the CAG repeat in the Huntingtin gene can change over a person’s lifetime in some cells of the body, particularly in the brain.. 
2. The process of switching on the HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 gene was causing somatic instabilitysomatic expansion A process in which the CAG repeat in the Huntingtin gene can change over a person’s lifetime in some cells of the body, particularly in the brain., and by reducing transcriptiontranscription the first step in making a protein from the recipe stored in a gene. Transcription means making a working copy of the gene from RNA, a chemical messenger similar to DNA., ASOsASOs A type of gene silencing treatment in which specially designed DNA molecules are used to switch off a gene reduced somatic instabilitysomatic expansion A process in which the CAG repeat in the Huntingtin gene can change over a person’s lifetime in some cells of the body, particularly in the brain.. 

To find out how ASOsASOs A type of gene silencing treatment in which specially designed DNA molecules are used to switch off a gene might affect somatic instabilitysomatic expansion A process in which the CAG repeat in the Huntingtin gene can change over a person’s lifetime in some cells of the body, particularly in the brain., the researchers injected a similar molecule into mice, called siRNAsiRNA A way of silencing genes using specially designed molecules of RNA – like DNA but made of only a single strand – that target the message molecules in cells and tell them not to make a certain protein, which reduces HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 protein but does not affect transcriptiontranscription the first step in making a protein from the recipe stored in a gene. Transcription means making a working copy of the gene from RNA, a chemical messenger similar to DNA.. When HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 protein levels were lowered using siRNAsiRNA A way of silencing genes using specially designed molecules of RNA – like DNA but made of only a single strand – that target the message molecules in cells and tell them not to make a certain protein, they did not see any effect on somatic instabilitysomatic expansion A process in which the CAG repeat in the Huntingtin gene can change over a person’s lifetime in some cells of the body, particularly in the brain.. This doesn’t mean siRNAsiRNA A way of silencing genes using specially designed molecules of RNA – like DNA but made of only a single strand – that target the message molecules in cells and tell them not to make a certain protein wasn’t exerting a beneficial effect, just that siRNAsiRNA A way of silencing genes using specially designed molecules of RNA – like DNA but made of only a single strand – that target the message molecules in cells and tell them not to make a certain protein wasn’t reducing somatic instabilitysomatic expansion A process in which the CAG repeat in the Huntingtin gene can change over a person’s lifetime in some cells of the body, particularly in the brain. in the cells the team looked at. However, it does indicate that ASOsASOs A type of gene silencing treatment in which specially designed DNA molecules are used to switch off a gene are slowing CAG growth by disrupting transcriptiontranscription the first step in making a protein from the recipe stored in a gene. Transcription means making a working copy of the gene from RNA, a chemical messenger similar to DNA., and not by lowering protein levels. 

Fewer Deliveries, Less Potholes?

To visualize the difference between siRNAsiRNA A way of silencing genes using specially designed molecules of RNA – like DNA but made of only a single strand – that target the message molecules in cells and tell them not to make a certain protein and ASOsASOs A type of gene silencing treatment in which specially designed DNA molecules are used to switch off a gene, imagine the HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 gene as an old road traveled by semi-trucks making deliveries, and the packages represent mRNAmessenger RNA A message molecule, based on DNA, used by cells as the final set of instructions for making a protein. messages. With each year that the road is driven on, its potholes and cracks worsen, just as HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15’s CAG repeatCAG repeat The stretch of DNA at the beginning of the HD gene, which contains the sequence CAG repeated many times, and is abnormally long in people who will develop HD worsens the more it’s used to make protein. Reducing HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 levels with siRNAsiRNA A way of silencing genes using specially designed molecules of RNA – like DNA but made of only a single strand – that target the message molecules in cells and tell them not to make a certain protein is like reducing the number of packages, but the same number of trucks are still on the road – they are just emptier! ASOsASOs A type of gene silencing treatment in which specially designed DNA molecules are used to switch off a gene, however, reduce the number of trucks, and fewer trucks mean less wear and tear on the road, and thus slower CAG growth. 

The researchers tried a more direct approach to test the connection between somatic instabilitysomatic expansion A process in which the CAG repeat in the Huntingtin gene can change over a person’s lifetime in some cells of the body, particularly in the brain. and transcriptiontranscription the first step in making a protein from the recipe stored in a gene. Transcription means making a working copy of the gene from RNA, a chemical messenger similar to DNA.. They turned to a genetically modified mouse model of HD where HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 transcriptiontranscription the first step in making a protein from the recipe stored in a gene. Transcription means making a working copy of the gene from RNA, a chemical messenger similar to DNA. can be switched on or off, like a switch, by adding a special chemical to their drinking water. In mice where HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 transcriptiontranscription the first step in making a protein from the recipe stored in a gene. Transcription means making a working copy of the gene from RNA, a chemical messenger similar to DNA. was switched off, they observed somatic instabilitysomatic expansion A process in which the CAG repeat in the Huntingtin gene can change over a person’s lifetime in some cells of the body, particularly in the brain. slowing down. In addition, the longer HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 transcriptiontranscription the first step in making a protein from the recipe stored in a gene. Transcription means making a working copy of the gene from RNA, a chemical messenger similar to DNA. was turned off, the less the CAG repeats grew. These results, in addition to their ASOASOs A type of gene silencing treatment in which specially designed DNA molecules are used to switch off a gene experiments, provided good evidence that transcriptiontranscription the first step in making a protein from the recipe stored in a gene. Transcription means making a working copy of the gene from RNA, a chemical messenger similar to DNA. was partially responsible for somatic instabilitysomatic expansion A process in which the CAG repeat in the Huntingtin gene can change over a person’s lifetime in some cells of the body, particularly in the brain.. 

Zinc Finger Roadblocks

Although switching HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 on or off by adding a chemical to drinking water sounds fantastic, it only works in this specific type of genetically modified mice, which we sadly are not! So the researchers turned to a more practical approach using Zinc Finger Proteins (ZFPs), which are genetically modified proteins that attach directly onto CAG repeats and block transcriptiontranscription the first step in making a protein from the recipe stored in a gene. Transcription means making a working copy of the gene from RNA, a chemical messenger similar to DNA.. From our analogy, ZFPs are like giant roadblocks cutting off traffic. If the delivery trucks driving over the road (representing transcriptiontranscription the first step in making a protein from the recipe stored in a gene. Transcription means making a working copy of the gene from RNA, a chemical messenger similar to DNA.) are causing the potholes to worsen (CAG growth), then halting the traffic should slow somatic instabilitysomatic expansion A process in which the CAG repeat in the Huntingtin gene can change over a person’s lifetime in some cells of the body, particularly in the brain.. 

To test ZFPs, they used a virus to deliver their DNA instructions into mouse brains. One side of the mouse’s brain got a version of the ZFP that latches onto the CAG repeatCAG repeat The stretch of DNA at the beginning of the HD gene, which contains the sequence CAG repeated many times, and is abnormally long in people who will develop HD and shuts down transcriptiontranscription the first step in making a protein from the recipe stored in a gene. Transcription means making a working copy of the gene from RNA, a chemical messenger similar to DNA., and the other side got a version of the ZFP that binds HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 but does not shut down transcriptiontranscription the first step in making a protein from the recipe stored in a gene. Transcription means making a working copy of the gene from RNA, a chemical messenger similar to DNA.. The ZFPs that block transcriptiontranscription the first step in making a protein from the recipe stored in a gene. Transcription means making a working copy of the gene from RNA, a chemical messenger similar to DNA. showed an impressive 70% reduction in somatic instabilitysomatic expansion A process in which the CAG repeat in the Huntingtin gene can change over a person’s lifetime in some cells of the body, particularly in the brain.. Surprisingly, ZFPs that bind to HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 but don’t block transcriptiontranscription the first step in making a protein from the recipe stored in a gene. Transcription means making a working copy of the gene from RNA, a chemical messenger similar to DNA. still had a modest 42% reduction in somatic instabilitysomatic expansion A process in which the CAG repeat in the Huntingtin gene can change over a person’s lifetime in some cells of the body, particularly in the brain.. This is good news because completely shutting down HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 transcriptiontranscription the first step in making a protein from the recipe stored in a gene. Transcription means making a working copy of the gene from RNA, a chemical messenger similar to DNA. might be unsafe because HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 still performs important functions inside brain cells. So keeping HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 partially on while slowing somatic instabilitysomatic expansion A process in which the CAG repeat in the Huntingtin gene can change over a person’s lifetime in some cells of the body, particularly in the brain. might represent a safer therapeutic approach. 

Therapeutic Directions

Collectively, these results show that dialing down HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15’s transcriptiontranscription the first step in making a protein from the recipe stored in a gene. Transcription means making a working copy of the gene from RNA, a chemical messenger similar to DNA. not only reduces the amount of toxic HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 protein in the cell but might also slow its CAG growth. Although slowing CAG growth sounds like a home run, it’s important to reiterate that we still don’t know for sure if somatic instabilitysomatic expansion A process in which the CAG repeat in the Huntingtin gene can change over a person’s lifetime in some cells of the body, particularly in the brain. is causing disease onset – it’s just a promising lead! In addition, reducing HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 transcriptiontranscription the first step in making a protein from the recipe stored in a gene. Transcription means making a working copy of the gene from RNA, a chemical messenger similar to DNA., which was linked to slowed somatic instabilitysomatic expansion A process in which the CAG repeat in the Huntingtin gene can change over a person’s lifetime in some cells of the body, particularly in the brain., might cause entirely unrelated problems in the cell. In our analogy, blocking package deliveries would stop the potholes from forming, but this would also surely create an angry bunch of customers waiting for their packages! 

Clinical trials using ASOsASOs A type of gene silencing treatment in which specially designed DNA molecules are used to switch off a gene are already underway, and therapies based on ZFP are being worked on. Although there’s plenty of room for optimism, there are some important caveats. First of all, the mice used in these experiments are genetically engineered with an extreme CAG repeatCAG repeat The stretch of DNA at the beginning of the HD gene, which contains the sequence CAG repeated many times, and is abnormally long in people who will develop HD mutation, because they otherwise wouldn’t show symptoms due to their short lifespan. And whether these therapies will translate effectively or safely into humans is another big question mark. For example, although ASOsASOs A type of gene silencing treatment in which specially designed DNA molecules are used to switch off a gene and ZFPs might be tolerated within the very short lifespan of a mouse, we don’t know the long-term safety or effectiveness in humans. Regardless, we’ll be following every development closely and sharing updates as soon as they are released! 

Summary

• CAG repeats in the HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 gene keep expanding over life, and this somatic instabilitysomatic expansion A process in which the CAG repeat in the Huntingtin gene can change over a person’s lifetime in some cells of the body, particularly in the brain. may contribute to HD’s delayed onset.
• ASOASOs A type of gene silencing treatment in which specially designed DNA molecules are used to switch off a gene treatments slow repeat expansion by reducing HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 transcriptiontranscription the first step in making a protein from the recipe stored in a gene. Transcription means making a working copy of the gene from RNA, a chemical messenger similar to DNA., not just HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 protein levels.
• Multiple experiments, including siRNAsiRNA A way of silencing genes using specially designed molecules of RNA – like DNA but made of only a single strand – that target the message molecules in cells and tell them not to make a certain protein, switchable transcriptiontranscription the first step in making a protein from the recipe stored in a gene. Transcription means making a working copy of the gene from RNA, a chemical messenger similar to DNA., and Zinc Finger Proteins, confirm that less HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 transcriptiontranscription the first step in making a protein from the recipe stored in a gene. Transcription means making a working copy of the gene from RNA, a chemical messenger similar to DNA. means less CAG growth.
• Therapies targeting transcriptiontranscription the first step in making a protein from the recipe stored in a gene. Transcription means making a working copy of the gene from RNA, a chemical messenger similar to DNA. look promising, but it’s still unclear whether slowing somatic instabilitysomatic expansion A process in which the CAG repeat in the Huntingtin gene can change over a person’s lifetime in some cells of the body, particularly in the brain. will change HD onset in humans.

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Suppression of Huntington’s Disease Somatic Instability by Transcriptional Repression and Direct CAG Repeat Binding