Huntington’s Disease
Huntington’s Disease is fatal, currently incurable, degenerative disease that primarily impacts the brain. It arises from a specific mutation – an expansion of a long stretch of repeated C-A-G nucleotides in a gene that we now call “Huntingtin”. In 1993, researchers discovered that every single HD patient has an expansion in this long repetitive sequence above a certain threshold around 40 CAG repeats. Unfortunately, while much progress has been made on understanding the mechanisms by which the HD mutation impacts model systems, we don’t yet have any disease-modifying treatments for HD.
The symptoms of HD generally present in mid-life, although a relatively small subset of HD patients have onset before the age of 18 and are therefore considered to have “juvenile HD”. People with HD experience a progressive worsening of a wide range of symptoms, which tend to cluster in three distinct domains: 1) movements – HD patients have a number of movement changes, particularly a writhing dance-like motion called chorea; 2) thinking – HD causes a wide range of progressive changes in cognitive ability; 3) mood – HD is associated with many different changes in mood – depression, irritability and apathy are commonly observed. The Huntington’s Disease Soceity of America has outstanding basic information about HD here.
The primary goal of the work in the Carroll lab, as well as in the broader HD community, is to try and slow, or even halt, the progression of HD symptoms in people carrying the mutation.
Our HD Model Systems and Techniques
We primarily use mouse and cellular models to conduct our research. We utilize knock-in mouse models of HD, in which a long CAG tract has been knocked into the mouse Huntingtin locus, to conduct our studies of the impact of this mutation, and how those impacts ultimately become pathogenic. We often conduct cellular experiments, most often using either primary or immortalized cells derived from our HD mouse model. We use a broad range of molecular, cellular and physiological assays to assess how our cell and animal models are doing.
Antisense Oligonucleotides
We have worked for many years with a therapeutic modality called antisense oligonucleotides, or ASOs. ASOs are short, chemically modified oligonucleotides that can be designed to bind and modulate cellular RNA’s via several mechanisms. Most simply, a “gapmer” design including a central stretch of deoxy nucleotides are flanked by modified “wings” of 2′-modified bases. These have the capability of driving cleavage of target genes whose messenger RNA contains the reverse-complement of the ASO sequence by the ubiquitous cellular enzyme RNAseH, which cleaves RNA/DNA hybrid structures. Other modes of action are possible – in fact Nusinersen (Spinraza) revolutionized treatment for spinal muscular atrophy patients when it was found to provde robust protection in that fatal disease – does not work via this RNAseH-mediated mechanism, but rather by modulating splicing of SMN2.
Other Rare Disorders
Recently, given our background in HD, we have begun work in hopes of helping hasten therapies for other rare neurodegenerative disorders. We have developed a novel mouse model Dentatorubral-pallidoluysian atrophy (DRPLA), another disease caused by an expansion of a long CAG tract, this time in the Atrophin-1 gene. Studies ongoing in the lab are testing silencing of the ATN1 gene in our novel mouse model is associated with any beneficial changes in DRPLA-like symptoms in our new mouse model. In addition to our preclinical work, we are deeply involved with the DRPLA effort via supporting the CureDRPLA foundation in their many clinical and pre-clinical initiatives focused on this disease.
n-Lorem
The n-Lorem foundation was established in 2020 with the goal of providing ASO-based drugs to patients with nano-rare diseases – fewer than 30 patients across the world. Not every genetic disease, or patient, is amenalbe to treatment by ASOs, but for those that are, the goal of the foundation is to identify such a drug, and provide it to the patient for free, for life. At UW, Dr. Carroll spends a fraction of his time working with n-Lorem, with a particular focus on vetting cases for n-Lorem’s Access to Treatment Committee (ATTC).