By: Lise Munsie, PhD
At the 7th Annual CHDI HD Therapeutics Conference in Palm Springs, California, scientists from academia and industry convened to discuss the current state of drug development research aimed at slowing the progression of Huntington disease (HD). Robert Pacifici, CHDI’s chief scientific officer, opened the conference.
The first session of the meeting reviewed the relevance of systems biology to HD research. The opening talks by Lee Hood and Keith Elliston, CHDI’s vice president of Systems Biology, outlined the systems biology field and suggested whole genome sequencing of HD families to gain more genetic information about the processes that affect HD phenotypes. Elliston specifically described ways that CHDI is already using this technology. Jim Gusella discussed the discovery of genes that modify the age of onset in HD. The session ended with Hanchuan Peng, who described the “3D neuronal atlas” model that his group is developing to quantitatively measure synapses.
The next session focused on post-translational regulation of the huntingtin protein. Melissa Moore opened the session by reviewing recent work that examines the toxicity of CAG expansions in RNA; the possibility of toxic RNA in HD; and posed the idea of targeting the RNA to knock down mutant huntingtin (mHtt) levels. Naoko Tanese reviewed recent reports of huntingtin functioning at sites of local translation in distal parts of the cell, and indicated that huntingtin traffics RNA to these sites. Lisa Ellerby and Dimitri Krainc examined the classic post-translational modifications of huntingtin and how these modifications may be drug targets. Marcy MacDonald ended the session by describing how her group has screened the full-length protein for novel post-translational modifications and has assigned signatures to mHtt vs. wildtype huntingtin.
Session three highlighted current efforts to silence the expression of mHtt. Beverly Davidson showed published results that highlight the safety and efficacy of RNA interference in the primate brain. Frank Bennett (see interview on page 8) from Isis Pharmaceuticals described his work on using antisense oligonucleotides (ASO) to silence the expression of mHtt, and discussed possible efficacy of ASOs in the brain, administered by infusion into the cerebrospinal fluid. Steve Zhang highlighted Sangamo BioScience’s successful efforts in using zinc finger protein transcription factors in other diseases and talked about the recent efforts of the company in using this technology in allele-specific silencing. William Kaemmerer described the biomarkers necessary to test the efficacy of these therapies in humans. Neil Aronin described the efforts of his group to refine technical procedures that will enable therapies utilizing adeno-associated viral delivery of small RNAs to become a reality.
The keynote address was given by Ann Graybiel, who described her efforts to understand the cortico-striatal pathways and their potential for manipulation. Following her talk, a session on small molecule drug discovery featured efforts by different drug companies, such as Pfizer’s previous work on phosphodiesterase inhibitors. CHDI’s Varhi Beaumont described their assays in HD mice testing Pfizer’s drugs and discussed the collaboration between their two organizations. Ladislav Mrzljak described CHDI’s investigations on kyneurine 3-monooxygenase inhibitors. To finish the session, Graeme Bilbe from Novartis highlighted recent efforts in characterization of an mGLu5 receptor agonist that has previously been effective in multiple models of neurodegeneration.
The final session gave an excellent overview of clinical perspectives of HD. Cristina Sampaio from CHDI described the group work currently in place to achieve the company’s goal of running “smart trials”. Sarah Tabrizi outlined the three-year results from the TRACK-HD study, including endpoints that can be used in clinical trials, and introduced the follow-up Track-On-HD study. Mark Guttman discussed the clinical onset of HD symptoms and asked whether current diagnostic criteria should be changed. In the final talk, Michael Hayden discussed the actual prevalence of HD. A detailed study conducted in British Columbia revealed a gross underestimation of the prevalence of HD in that population.