Huntington's disease therapeutics conference 2019 – Day 2

Jeff and Ed report from the Huntington’s Disease Therapeuticstherapeutics treatments Conference – the biggest annual gathering of HD researchers. This year’s conference is bigger and more exciting than ever.

Read about Day 1 here.

Advanced tools for translational research

Morning everyone! The second day of the 2019 HD Therapeuticstherapeutics treatments Conference is kicking off in Palm Springs. The first session is “advanced tools for translational research”.

The first speaker today is Lauren Byrne from UCL who studies biomarkers in blood and cerebrospinal fluidCSF A clear fluid produced by the brain, which surrounds and supports the brain and spinal cord.. Byrne measured mutant Huntingtin in CSFCSF A clear fluid produced by the brain, which surrounds and supports the brain and spinal cord., and neurofilament lightNfL biomarker of brain health protein in CSFCSF A clear fluid produced by the brain, which surrounds and supports the brain and spinal cord. and blood in 80 volunteers. Neurofilament lightNfL biomarker of brain health or NFLNfL biomarker of brain health is a protein found in neuronsneuron Brain cells that store and transmit information and released when they are damaged. Byrne also did MRImagnetic resonance A technique using powerful magnetic fields to produce detailed images of the brain in living humans and animals scans to see how each biomarkerbiomarker a test of any kind – including blood tests, thinking tests and brain scans – that can measure or predict the progression of a disease like HD. Biomarkers may make clinical trials of new drugs quicker and more reliable. predicts brain shrinkage. Surprisingly, neurofilament turns out to be a better predictor the mHTT of clinical symptoms and brain volume. Changes in these “biofluid” markers were among the earliest detectable changes too, preceding imaging and clinical measures in the sequence of events in HD.

Byrne has now completed the 2-year follow ups from the HD-CSFCSF A clear fluid produced by the brain, which surrounds and supports the brain and spinal cord. study and shows that the NFLNfL biomarker of brain health seems to be changing as expected over time, and can be measured using a new system that tests 4 molecules at once.

Next up is Amber Southwell, from UCF, who is also interested in developing tools to quantify mutant huntingtin in the spinal fluid. Southwell’s team was the first to show that when mice are treated with a Huntingtin lowering therapy – specifically an ASOASOs A type of gene silencing treatment in which specially designed DNA molecules are used to switch off a gene from Ionis Pharma – levels of mutant Huntingtin in the spinal fluid are reduced. This is important – it means that when we treat human HD patients with Huntingtin lowering drugs, we’d predict that the levels of mutant Huntingtin in the spinal fluid will go down. This is one of the things reserarchers mean when they say a measurement is a “biomarkerbiomarker a test of any kind – including blood tests, thinking tests and brain scans – that can measure or predict the progression of a disease like HD. Biomarkers may make clinical trials of new drugs quicker and more reliable.”.

Southwell’s team is doing a cool series of experiments with mice that have no Huntingtin in specific types of brain cells. This is enabling them to map the exact type of brain cell responsible for releasing mutant Huntingtin into the spinal fluid.They’re also conducing another set of experiments focused on understanding the exact process by which mutant Huntingtin makes its way from brain cells called neuronsneuron Brain cells that store and transmit information into the spinal fluid. One process of brain bathing called “glymphatic clearance” seems likely to play a role in mutant Huntingtin making it’s way into the spinal fluid.

Next is David Salzman of sRNAlytics, a company that investigates the use of RNARNA the chemical, similar to DNA, that makes up the 'message' molecules that cells use as working copies of genes, when manufacturing proteins. to study diseases.RNARNA the chemical, similar to DNA, that makes up the 'message' molecules that cells use as working copies of genes, when manufacturing proteins. is the single-stranded cousin of DNA. Cells use RNARNA the chemical, similar to DNA, that makes up the 'message' molecules that cells use as working copies of genes, when manufacturing proteins. for many functions, most famously as the “working copy” of genes they want to switch on. That’s called messenger RNAmessenger RNA A message molecule, based on DNA, used by cells as the final set of instructions for making a protein.. Less famously, cells produce many small RNARNA the chemical, similar to DNA, that makes up the 'message' molecules that cells use as working copies of genes, when manufacturing proteins. molecules that help in the regulation of gene switching. They have names like microRNA and there are lots of different ones.We understand genes as recipes for proteins pretty well, but micro RNAs are much morel mysterious at the moment.

SRNAlytics identifies patterns of small RNARNA the chemical, similar to DNA, that makes up the 'message' molecules that cells use as working copies of genes, when manufacturing proteins. changes and uses artificial intelligence algorithms to identify what part of the body they come from, and how they change in different diseases. A panel of 60 small RNAs in CSFCSF A clear fluid produced by the brain, which surrounds and supports the brain and spinal cord. can apparently distinguish between Huntington’s, Alzheimer’s and Parkinson’s with decent accuracy. Two small RNAs are of particular interest in HD, but it’s important to understand exactly what they do in healthy and HD brains in order to figure out their value as possible biomarkers.

New animal models

Guoping Feng, from MIT, is up next. His lab is working on developing new primateprimate a group of mammal species including monkeys, apes and humans models of HD. He says mice are very useful, but they don’t have all the same brain regions as humans, so we need to study more sophisticated brains as well. It used to be difficult to impossible to genetically modify primates, like monkeys, but new genomegenome the name given to all the genes that contain the complete instructions for making a person or other organism engineering tools make it possible. Tools like CRISPR/Cas9CRISPR A system for editing DNA in precise ways allow precise DNA edits to be made to the DNA of monkey embryosembryo the earliest stage during the development of a baby, when it consists of just a few cells. Feng’s lab is one of the world’s best at making changes to primateprimate a group of mammal species including monkeys, apes and humans DNA. He describes that they’ve learned from human IVFIn vitro fertilization A medical procedure where eggs and sperm are combined in the laboratory, then embryos are implanted in the mother's womb. clinics the best ways to keep primateprimate a group of mammal species including monkeys, apes and humans embryosembryo the earliest stage during the development of a baby, when it consists of just a few cells healthy. Feng’s lab has generated a novel monkey model of a genetic form of autism. These monkeys have very interesting behaviors that really resemble humans with Autism, including altered social behaviors. They are now working to develop a monkey model of Huntington’s Disease, and have conducted initial experiments suggesting it should be possible.

Hideyuki Okano, of Keio University, also works on primateprimate a group of mammal species including monkeys, apes and humans models of human diseases – specifically Marmosets. His lab has genetically modified Marmosets to have a form of Parkinson’s Disease caused by a genetic mutation. These animals have symptoms very close to those observed in Parkinson’s Disease patients, including a very challenging sleep condition called REM sleep behavior disorder (RBD). They also have tremors and walking problems that resemble Parkinson’s Disease patients. It’s a good argument for using more more sophisticated animals to model progressive brain diseases. Okano’s lab is now developing techniques to generate similar models for Huntington’s Disease.

Thats all for today! Be sure to check out our write up of day 1 here and stand by for our final roundup tomorrow.