From Malta to the Vatican
A report from two recent events that highlight how and why we do Huntington’s research
As part of a drug discovery research team that works closely with the Huntington’s disease foundation CHDI, I had the opportunity along with a dozen of my colleagues from the UK, The Netherlands and Finland to attend the 12th HD Therapeutics Conference in Malta last month. CHDI holds this international meeting yearly; this time over 350 scientists from pharmaceutical, biotech and academic laboratories—as well as CROs—gathered to discuss the latest research developments.
HD is an inherited neurodegenerative condition characterized by movement disorders, neuropsychiatric features, and dementia. A genetic lesion in the Huntingtin gene that provides information for the protein huntingtin causes uncontrolled repeats of the cytosine-adenine-guanine triplets. This leads to an abnormally long polyglutamine (polyQ) expansion in the huntingtin (Htt) protein. Yet while we know what mutation causes Huntington’s the mechanisms driving the progression of HD’s clinical features are not fully understood.
The scientific content of the CHDI meeting was excellent. Some of the highlights included talks about the continued insights into the genetics behind HD and alternative approaches to somatic expansion in HD, including new and emerging targets for intervention.
Genetic Variation studies
The search for genetic differences in genes other than the Huntingtin gene (so called genetic modifiers), is also producing interesting results, reports Jones of Cardiff University, who was part of the GeM-HD study published in 2015. Key findings from the study, which analyzed DNA samples from about 4,000 HD patients, are that genetic variations in DNA repair genes influence the age at which HD symptoms occur, showing that the process of DNA repair is becoming more and more relevant in disease progression. Leslie highlighted that HD-associated modifying variants in the DNA damage response are also present in other repeat expansion-associated disorders (e.g. spinocerebellar ataxias, SCA). She showed that genes of the DNA damage response significantly modify age at onset in HD and SCA, suggesting a common pathogenic mechanism which operates on the CAG expansion in the DNA of the genes. Davina Hensman Moss of University College London used information from the TRACK-HD study to understand how disease progression happens. They generated a progression score based on principal component analysis of prospectively acquired longitudinal changes in motor, behavioral, cognitive and imaging and found again that variations in DNA repair genes changes the rate of HD progression.
The meeting also highlighted new ways of potentially reversing progression of disease. Among the potential strategies being looked at to target the mutant Huntingtin gene and the protein associated with the disease involves a more innovative way of lowering mutant HTT messenger RNA levels in the brain. Kevin Weeks from the University of North Carolina- Chapel Hill reported on ongoing studies examining the structure of HTT mRNAs from native cellular RNA and their target ability by small molecules.
Possibly the most significant talk of the meeting came from Andrew Yoo from Washington University in St. Louis. Dr. Yoo has come up with a way of directly converting fibroblasts into neurons in a cellular model to study HD. The direct transdifferentiation of an HD patient’s fibroblasts to medium spiny neurons resulted in neurons with HD inclusions and mHTT-dependent cell death, but which also maintained epigenetics of the adult patients.
This is significant because none of these findings are observed in stem cell-derived neuronal models from disease relevant (40 – 45Q) Q lengths. They do not form aggregates; the neurons don’t die as presumably epigenetic age is reset during conversion from fibroblast to stem cells. This approach has the potential to give us, for the first time, an in vitro system that can test whether potential therapeutic targets will impact mHTT aggregate formation, neuronal dysfunction and induced neuronal death in patient-derived cells. This strategy outlined by Dr. Yoo should better reflect the clinical situation in patients and potentially lead to novel treatments that have a better chance of translating from the bench to the bedside.
The work of Charles River was also highlighted in a number of talks, including Kimmo Lehtimӓki’s award-winning poster. Lehtimӓki, who works at our Discovery site in Kuopio, Finland, won the second prize for his work on animal models for Huntington’s Disease.
The Human Face of Huntington’s
While just 5 to 10 people per 100,000 are estimated to be affected by HD globally, the Maracaibo region in northwestern Venezuela has a much higher prevalence, about seven cases per 100. In nearby Columbia, HD patients live in extreme poverty. HDdennomore (pronounced ‘Hidden No More’ or ‘Oculta Nunca Más’ in Spanish), a global coalition of many different patient advocates dedicated to raising awareness about HD and ending the stigma and shame around the disease, has made a powerful documentary about families in South America impacted by HD. On May 18 they took this project to the next level. Families from Colombia, Venezuela and Argentina flew to Rome, where Pope Francis recognized the devastating plight of those living with and affected by HD by hosting, at the Vatican, the world’s largest gathering of the HD community ever. I together with 10 other scientists from CRL shed our labcoats and flew to Rome to support this amazing event (group photo shown below.) It was overwhelming! Over 1500 people including 150 HD patients from all over the world, gathered together in the “Sala Nervi” to hear a strong message by the Pope in support of the HD community. ‘HIDDEN NO MORE!’ it should not be just a slogan but a real commitment. The organiser’s hope raising awareness of the plight of the South American families will lead to more help being given from the state, the church and more understanding from their communities. More information on this once in a lifetime event can be found at the HDdennomore website.