Highlights of CHDI
By: Lise Munsie, PhD
CHDI began this year’s conference with a pre-session where members discussed what was happening at the foundation. The session started with an update from Dr. Tom Vogt, Vice President of Discovery and Systems Biology, about ongoing work on large-scale systems biology in HD. Dr. Vogt mentioned in particular the large study analyzing genetic modifiers of HD, which has opened up a data-mine for drug discovery research (data can be accessed through http://www.HDinHD.org). Following this, Dr. Celia Dominguez, Vice President of Chemistry, gave an update on drug development efforts, while Chief Clinical Officer Dr. Cristina Sampaio, who is involved with Enroll-HD, gave an update on that registry and the potential for clinical trial enrollment.
The first science session of the meeting reviewed how studying the huntingtin protein (HTT) has generated therapeutic leads. Dr. Fred Saudou presented his work looking at the little-studied C-terminus of HTT, and how C-terminal truncations may affect BDNF trafficking through aberrant interactions with dynamin 1. Dr. Ihn Sik Seong updated attendees on the techniques he uses to purify full-length HTT, and the progress his group has made on structural modeling. The next session shifted focus from protein to nucleic acid. Dr. Steve Hovarth opened the session explaining his epigenetic clock, which uses DNA methylation to age tissues. He has found that DNA from HD brains appears older than DNA from control brains of the same chronological age. Dr. Vanessa Wheeler spoke about CAG somatic expansion, while Dr. Laura Ranum described how a phenomenon called “RAN-translation” occurs in protein products of genes with triplet repeats. Her team has identified this phenomenon when a CAG-expanded HTT allele is present. Dr. Ray Truant closed the session, describing unpublished work his group has done on DNA damage repair in HD.
The next session focused completely on targeted therapies for HTT-knockdown, a very popular topic at the conference. Dr. Ignacio Munoz from CHDI spoke specifically about CHDI-sponsored work that recognizes biomarkers that can be used to monitor HTT-knockdown in the brain. Dr. Feng Zhang, one of the individuals originally involved with discovering the CRISPR/Cas9 system, gave a web-conference on CRISPR, which is a potential new method for in vivo gene silencing. Dr. Eric Reits closed the session, describing how the proteasome might be used as an intracellular method for silencing mHTT.
The next session was an exciting clinical trials update that featured talks on four different ongoing trials. Dr. Neal Simon described Azevan’s trial of SRX246, which targets psychological symptoms. Dr. Marielle Delnomdedieu from Pfizer described the company’s ongoing trials of a PDE10A inhibitor (see HD Insights, Vol. 5) in collaboration with the Institut du Cerveau et de la Moelle épinière (ICM) in Paris. Dr. Maurice Zauderer from Vaccinex presented on the SIGNAL trial, which is investigating the use of a monoclonal antibody to block the activity of SEMA4D in HD patients (see HD Insights, Vol. 12). The session ended with an exciting talk by Dr. Sarah Tabrizi of University College London about the Phase I/IIa trial of IONIS-HTTRx, the first trial to evaluate the safety and tolerability of intrathecal antisense oligonucleotides in patients (see HD Insights, Vol. 13).
The final day of the conference featured an introductory session on regenerative medicine in HD. Dr. Ali Brivanlou spoke about his work using embryonic stem cells to study development. By using precise gene editing technology, he induced the HD mutation in his cell line to study the role of mHTT in development. Dr. Paola Arlotta spoke about techniques her group uses to directly re-program neuronal subtypes, and how this may be a potential therapy for HD. Dr. Steve Goldman finished the session with a presentation on glia. His group developed a murine model in which the glial cells express mHTT but the neurons do not, and he finds pathology in the brain in this system.
The final session of the conference focused on modeling using clinical data. Dr. Doug Langbehn, the statistician for the TRACK-HD study, opened the session by describing how to properly set up clinical trials. Dr. Tiago Mestre gave a follow-up talk describing how clinical rating tools can be translated into a scaling system for rating the progression of symptoms in HD. Dr. Jianying Hu gave the final talk of the conference, describing his work that uses machine-based learning to analyze the huge amounts of data involved in accurately diagnosing and assessing prodromal HD, which would be used in moving forward clinical trials and assessing outcomes in pre-symptomatic patients.