CHDI’s 10th Annual HD Therapeutics Conference took place February 23 – 26, 2015, in Palm Springs, California. This unique conference series focuses on drug discovery and development for Huntington’s disease, and draws participants and speakers from the biotech and pharmaceutical sectors as well as academia and research institutions. The conference is intended as a forum where all participants can share ideas, learn about new disciplines, network with colleagues and build new collaborative partnerships. We are indebted to all of the conference speakers, and especially grateful to those who are able to make their presentations available here for a wider audience.
- An Update on CHDI’s Preclinical Portfolio Robert Pacifici, PhD
- An Update on CHDI’s Clinical Portfolio Cheryl Fitzer-Attas, PhD
- Keynote Presentation Jeff Carroll, PhD
- Connectomic mapping of connectopathies in mouse models of Huntington’s disease Hongwei Dong, MD, PhD
- Cell type-specific molecular profiling and genetic screening in mouse models of Huntington’s disease Myriam Heiman, PhD
- Functional analysis of transcriptomic alterations in Huntington’s disease Juan Botas, PhD
- Medication of Huntington’s disease by genetic variations Jong-Min Lee, PhD
- Computational modeling of CAG length dependence in Huntington’s disease and launch of
HD in HD portal Jim Rosinski, PhD
- The multiple tissue molecular signature in HD (MTM-HD) project Michael Orth, MD, PhD
- Mitochondrial energetics and ROS production in models of Huntington’s disease Martin D. Brand, PhD
- 13C MRS studies reveal decreased neuronal mitochondrial oxidation and glutamate/GABA/glutamine cycling in mouse models of Huntington’s disease: Evidence for mitochondrial dysfunction? Douglas Rothman, PhD
- The role of discovery biochemical profiling in metabolic individuality and its application to Huntington’s disease Ryan D. Michalek, PhD
- Systems neuromedicine: Discovery of new pathobiologic networks and preclinical biomarkers Howard J. Federoff, MD, PhD
- Nrf2 as an emerging HD therapeutic target Larry C. Park, PhD
- Identifying small molecule modulators of mutant huntingtin protein levels in HD patient-derived cells George McAllister, PhD
- Huntingtin lowering through selective inhibition of Hsp90 a/β Dean Stamos, PhD
- Widespread gene delivery to the nonhuman primate brain for the treatment of Huntington’s disease Lisa Stanek, PhD
- Challenges in clinical translation for engineered zinc finger transcriptional repressors that selectively inhibit mutant huntingtin expression Geoff Nichol, MB, ChB, MBA, FRACP
- Antisense oligonucleotide therapies for the treatment of Huntington’s disease C. Frank Bennett, PhD
- A strategy for the identification of translatable HTT-lowering biomarkers Douglas Macdonald, PhD
- Challenges and opportunities at NINDS: Lessons learned Story Landis, PhD
- Towards the understanding of Huntington’s disease through lipidomics Gilbert Di Paolo, PhD
- Biomarkers and biological insights from Huntington’s disease patient cerebrospinal fluid Ed Wild, MD, PhD
- Automated speech analysis for diagnosis in psychiatry Guillermo Cecchi, PhD
- The role of precompetitive consortia, data sharing and regulatory science in catalyzing innovation for neurodegenerative diseases Diane Stephenson, PhD
- Pridopidine and laquinimod: Applying preclinical and clinical new insights for the treatment of HD Michal Geva, PhD
- Preferential vulnerability of highly connected brain regions to structural connectivity loss in HD and identification of novel brain compensation in preclinical HD — new findings from Track-ON HD Sarah J. Tabrizi, MD, PhD, FMedSci
Sarah Gregory, PhD
- Positron emission tomography in Huntington’s disease: New multi-modal approaches towards a definitive biomarker study Marios Politis, MD, MSc, DIC, PhD
- Huntington’s disease: Clinical trials 2014 Ray Dorsey, MD
- Randomized controlled trials (RCT’s) in Huntington’s disease in 2015: Unmet needs, challenges and hopes G. Bernhard Landwehrmeyer, MD, FRCP
An Update on CHDI’s Preclinical Portfolio
Robert Pacifici, PhD – CHDI
An Update on CHDI’s Clinical Portfolio
Cheryl Fitzer-Attas, PhD – CHDI
Jeff Carroll, PhD – Western Washington University
Mouse Genetic Approaches to Discover and Validate Molecular Targets for Huntington’s Disease
Hong-Wei Dong, MD, PhD – University of Southern California
Activity of a single brain structure alone is not sufficient to produce behavior. Instead, behaviors require the cooperative assembly of multiple neural circuits or networks. Therefore, in disease states, both individual structures and their projection sources and targets are affected. Such “connectopathies” have been implicated in neurological disorders, such as Huntington’s disease (HD) — an inherited neurodegenerative disorder with motor, psychiatric, and cognitive deficits. HD exhibits both cortical and striatal atrophy and neuronal loss as well as deficits in connections between cortical and striatal neurons. However, little is known about the aberrant neuroanatomical wiring in HD-afflicted brains and how these pathological connections correspond to motor and cognitive deficits as the disease progresses.
Recently, we launched a NIH-funded Mouse Connectome Project (MCP, www.MouseConnectome.org), which aims to generate a navigation roadmap of neural networks that link all structures within a standard, 3-dimensional atlas similar in concept to Google Earth. Towards this long-term objective, we have assembled neural networks of the mouse neocortex (Zingg et al., 2014) and constructed an unprecedented comprehensive cortico-striatal projection map. Together, this work provides insight into how cortical structures and their downstream striatal targets form networks to regulate behavioral output. This novel connectomic strategy can be applied to systematically characterize connectivity disruptions in HD mouse models and to correlate the development of pathway-specific deficits with the onset of behavioral phenotypes. Such an approach may help to explore diagnostic and therapeutic targeting of specific cortico-striatal pathways to alleviate disease symptoms.
Cell type-specific molecular profiling and genetic screening in mouse models of Huntington’s disease
Presentation not available
Myriam Heiman, PhD – Massachusetts Institute of Technology
Medium spiny neurons (MSNs) of the striatum are among the most vulnerable cell populations affected in Huntington’s disease. While transcriptional dysregulation in MSNs is a hallmark of HD, to date it has been unclear whether the two major populations of MSNs, which have been reported to display different vulnerabilities in human patients, display different transcriptional responses to mutant Huntingtin expression in mouse models. To address this question, we applied the translating ribosome affinity purification (TRAP) methodology, which reports cell type-specific translated mRNA profiles, to the study of mouse models of HD. We find that many striatal gene expression changes previously associated with mouse models of HD are present in our study of the two major MSN types, striatonigral and striatopallidal neurons. However, we additionally reveal many previously unreported cell-type specific changes to gene expression in both a full-length and exon 1 model of the disease. We find that the gene expression changes seen in response to mutant Huntingtin in each subtype of MSN are largely distinct but in each case show striatal specificity. With regard to regulators of the transcriptional responses observed in MSNs, our data implicate altered polycomb repressive complex 2 (PRC2) activity.
Although our TRAP study has identified many gene expression changes in these MSNs in mouse models of HD, in order to probe causative links to cell death in HD, we have also developed a new genetic screening methodology termed Synthetic Lethal In the Central nervous system, or SLIC. SLIC probes for synthetic lethal interactions with mutant Huntingtin by combining the use of mouse models of HD with injection of barcoded lentiviral knock-down libraries into the striatum. DNA sequencing is used to reveal barcoded elements that are lost or enriched after in vivo incubation, allowing assessment of synthetic lethality. A screen with 96 elements chosen from our MSN TRAP studies reveals that knock-down of Gpx6, a gene which is up-regulated with age but down-regulated in the striatum of HD mouse models, displays synthetic lethality with mutant Huntingtin. Finally, we show that Gpx6 overexpression in the striatum of R6/2 model mice ameliorates motor and molecular HD model phenotypes.
Functional analysis of transcriptomic alterations in Huntington’s disease
Juan Botas, PhD – Baylor College of Medicine
The wide application of microarray and RNAseq analyses to disease conditions is generating vast amounts of data that are expected to provide much needed insight into disease mechanisms and potential therapeutic avenues. To take full advantage of this wealth of data, we need to develop new approaches capable of testing the significance of the myriad of changes observed in gene expression profile studies. In this project we used functional analyses to query the potential significance of transcriptomic alterations in Huntington’s disease (HD). Using a behavioral readout in a Drosophila model we test the genes whose expression is altered during early stages of disease as potential modifiers of pathogenesis. The results from these tests allow us to define potential compensatory and pathogenic gene expression alterations. Network analyses reveal higher connectivity and higher correlation with disease progression among these two groups than among genes that do not appear to modify disease. These data point to unexpected approaches to alleviate HD pathogenesis and illustrates the value of integrating transcriptomic data with functional analyses in model systems.
Medication of Huntington’s disease by genetic variations
Jong-Min Lee, PhD – Massachusetts General Hospital, on behalf of the CHDI GeM Consortium
The HTT CAG trinucleotide repeat expansion mutation is both necessary and sufficient to cause the onset of the characteristic neurologic, cognitive or psychiatric signs of Huntington’s disease (HD). In general, the rate of the pathogenic process that leads to clinical manifestations is largely determined by CAG repeat size, though the wide range in age at onset that is observed for any given CAG repeat size strongly suggests the existence of disease-modifiers. We have used an unbiased genome-wide association study (GWAS) approach to discover genetic variants that are significantly associated with CAG-corrected age at onset of motor signs (i.e., residual age at onset). In total, 2.5 million SNPs were genotyped in approximately 4,000 HD subjects, and the association with the residual age at onset phenotype was tested, yielding the chromosomal locations of two genome-wide significant modifier loci. A region on chromosome 15 harbors two independent modifier signals, likely due to a single gene; one hastens age at onset by ~6 years, and the other delays age at onset by ~1.4 years. A region on chromosome 8 region carries a locus that delays onset by ~1.6 years. Furthermore, near-genome-wide association signals at the MLH1 region on chromosome 3 and the results of pathways analyses, which capture information from SNPs that singly do not meet genome-wide significance, suggests a potential role for DNA mismatch repair / maintenance processes in altering the course of HD. The modifier loci that have emerged thus far from the pool of natural genetic variants in ~4,000 HD subjects bode well for the continued success of a genetic route to the discovery of modifiers of the disease events that occur before clinical signs and offer HD subject-validated processes to be evaluated for the development of HD therapeutics.
Computational modeling of CAG length dependence in Huntington’s disease and launch of HD in HD portal
Jim Rosinski, PhD – CHDI
We have undertaken a multilayered approach to explore and understand the pathophysiology of Huntington’s disease and to bring forward new candidate therapeutic hypotheses. Knowledge of the causal gene and the allelic series of murine CAG repeat length expansion lines has been used to anchor our approach to build out a comprehensive and coherent dataset on which to perform a number of computational modeling approaches. Specifically in this presentation, we will focus on results obtained in collaboration with UCLA on validation of WGCNA-based models of mouse striatum and cortex, in collaboration with GNS Healthcare Bayesian causal models of the mouse striatum, and in collaboration with Psychogenics a relevance network based approach to link molecular endpoints to mouse behavioral phenotypes. We will describe experimental plans to refine the modeling efforts and initial efforts to identify candidate therapeutic interventions. Aligned with CHDI’s commitment to open source science, we will present the launch of our new HD in HD (HDinHD.org) portal, which will serve as a central hub where researchers can access, download, and interact with large datasets and interactive computational models of HD systems.
The multiple tissue molecular signature in HD (MTM-HD) project
Michael Orth, MD, PhD – Ulm University
Mitochondrial dysfunction has repeatedly been reported in Huntington’s disease (HD) brain but also peripheral tissues, including skeletal muscle. It remains unclear though what exactly constitutes the mitochondrial signature of HD. The MTM-HD project involves two HD sites, London led by Sarah Tabrizi and Ulm, and CHDI foundation. The aim is to investigate mitochondrial steady-state tissue signatures. This includes the potential of using omics (RNAseq, proteomics, metabolomics) data. In addition, we established primary cell lines. This will help dissecting cellular phenotypes and allows for cell-specific assessments of the response of intra-cellular systems to well-defined challenges. We sampled skeletal muscle, skin, adipose tissue and blood from near to motor onset pre-manifest HD (n=20), early onset HD patients (n=20) and sex and age matched healthy controls (n=20).
In skeletal muscle and adipose tissue MRC assembly and the activities of Complexes I, II/III and IV were similar in preHD, early HD and controls. This indicates that the presence of mutant HTT does not compromise the steady-state assembly and function of the MRC in preHD or early HD. Mitochondrial mass (measured with citrate synthase and mtDNA copy number) was also similar in all three groups as was TFAM protein and PGC1-α mRNA suggesting mitochondrial biogenesis is not altered. In early HD patients DRP1 levels (mRNA) were lower compared to pre HD patients. In early onset 9-month old HETQz175 mice Drp1 mRNA levels were also decreased in association with fewer mitochondria on electron microscopy. In addition in pre HD and early HD protein levels were increased of the short isoform of OPA1, an inner mitochondrial protein involved in mitochondrial fusion and mitophagy. This indicates that in early HD mice and human HD patients the mitochondrial fission and fusion balance differs from controls.
The next steps involve myoblasts and fibroblasts to investigate mitochondrial membrane potential (ΔΨm). ΔΨm is measured with or without pretreatment of cells with reagents that interfere with MRC function (e.g. MRC complex inhibitors) or induce intracellular oxidative stress. In addition, tissues will be used for RNAseq, proteomics and metabolomics analysis with appropriated bioinformatics to investigate more subtle metabolic signatures.
Mitochondrial energetics and ROS production in models of Huntington’s disease
Martin D. Brand, PhD – Buck Institute for Research on Aging
Mitochondrial dysfunction and altered reactive oxygen species (ROS) production are implicated in Huntington’s disease (HD). To explore mechanisms, we studied primary synaptosomes (nerve terminals) from HD mouse models, and mouse neuronal stem cells (mNSCs) expressing wild-type or polyQ-expanded huntingtin.
Synaptosomes have several advantages: nerve terminal function is probably relevant to HD; samples can come from adults; mitochondria retain their cellular environment; and little material (1-2 mice) is required. Striatal and cortical synaptosomes were prepared from symptomatic mouse models; R6/2, YAC128, BAC100, and particularly HdhQ175 (WT and homozygous Q175 knockin mice aged 5, 10, and 15 months, and heterozygous Q175 knockin mice aged 10 months). Bioenergetic function was assessed by Seahorse respirometry (cell respiratory control) in normal incubations and during bioenergetic stress (veratridine-stimulated ATP turnover). Results were corrected for any differences in synaptosomal number or quality. There was no bioenergetic deficit in HD synaptosomes; if anything, maximum respiratory capacity increased slightly. To determine if selective loss of damaged synaptosomes during preparation might mask dysfunction, we developed a 13C6/12C6-lysine labeling strategy. 10-15% more Q175 than WT striatal and cortical synaptosomes were lost during preparation, but this was insufficient to mask any large global bioenergetic deficit.
We investigated ROS levels in Q140 and Q7 mNSCs derived from genetically-manipulated mouse embryonic stem cells. We confirmed that a conventional ROS probe, DCFDA, gave a larger signal in the Q140 mNSCs. However, after correction for probe uptake, the levels of ROS reported by DCFDA were lower in Q140 cells, because of higher antioxidant defenses. We are exploring whether higher defenses reflect chronic higher ROS production rates, whether the capacity of mitochondria isolated from mNSCs to generate ROS at different sites in substrate oxidation and the electron transport chain differs, and whether novel suppressors of mitochondrial ROS production can normalize ROS in mNSCs.
13C MRS studies reveal decreased neuronal mitochondrial oxidation and glutamate/GABA/glutamine cycling in mouse models of Huntington’s disease: Evidence for mitochondrial dysfunction?
Douglas Rothman, PhD – Yale University School of Medicine
Evidence for alterations in brain mitochondrial energy metabolism, including reduced glucose utilization, has been observed in Huntington’s disease (HD) and HD animal models. However direct measurements of brain mitochondrial energy metabolism in living animals and patients have not been performed. Furthermore if there is reduced mitochondrial oxidative energy production it could be secondary to a reduction in neuronal demand as opposed to a reduction in mitochondrial capacity. Over the last two decade we have helped develop 1H –13C MRS in combination with 13C isotopically labeled substrates as a method for measuring rates of neuronal and glial mitochondrial oxidation and the rates of glutamate–glutamine and GABA-glutamine neurotransmitter cycles. Recently we applied these methods to test whether neuronal and glial mitochondrial metabolism and function are altered in two transgenic mouse models of HD expressing mutant huntingtin (a zQ175 and R6/2).
In both models we measured substantial drops in the mitochondrial TCA cycle in GABAergic and glutamatergic neurons with disease progression from pre manifest to manifest. Although the largest changes were seen in the striatum significant reductions were measured in the cortex and thalamus particularly in the manifest stage (52 weeks for the zQ175 and 8 weeks for the R6/2 mice). There was also a reduction in the glutamate and GABA neurotransmitter cycles indicating reduced neuronal signaling activity. No significant alteration was measured in glial metabolism suggesting that the impact of the mutant huntingtin expression on metabolism was primarily neuronal. We also observed changes in levels in glutamine and taurine suggesting that they may be valuable biomarkers for disease progression.
Because MRS, similar to MRI, can be performed in vivo these findings can be directly translated to human studies. In my talk in addition to describing the mouse studies I will discuss the potential for performing 13C and 1H MRS studies in patients. I will also address the question of whether we can determine experimentally in patients whether a reduction in mitochondrial activity is due to mitochondrial dysfunction or alternatively due to reduced energy demand.
The role of discovery biochemical profiling in metabolic individuality and its application to Huntington’s disease
Ryan D. Michalek, PhD – Metabolon Inc.
Understanding the role of genetic predispositions and their interaction with environmental factors in complex diseases is key to the development and monitoring of diagnostic tests and efficacious therapies. In the case of the neurodegenerative disorder Huntington’s disease, this genetic condition is characterized by mutant Huntingtin (mHtt) protein which can contribute to neuronal decay. Although predictive genetic testing can identify individuals who carry the gene defect before the onset of symptoms, without robust and practical measures of disease progression (biomarkers), understanding of disease progression and the evaluation of therapeutic interventions are limited. The Q175 mouse model of Huntington’s disease contains a knock-in of human mHtt and exhibits symptoms of partial motor impairment as early as 3 to 4 months of age with brain atrophy and metabolite changes by 1 year. In this study, striatum, cerebellum, cortex, gastrocnemius muscle tissue, and plasma were harvested from ~1 year old wild-type (WT) and Q175 mice and analyzed via untargeted mass spectrometry to establish a biochemical signature of Huntington’s disease.
These findings identified metabolic markers of enhanced glycolytic metabolism in Q175 cerebellum and striatum that may reflect increased glycolytic enzyme activity. Furthermore, altered glucose utilization may limit substrate availability for pentose phosphate pathway metabolism, consequently contributing to increased oxidative stress observed in the brain, muscle, and plasma of Q175 mice. Additionally, differences in tryptophan metabolism between genotypes may reflect increased inflammation in Q175 mice and impact serotonin production in the brain and muscle that may impact tissue integrity. Q175 muscle tissue also possessed a metabolic signature associated with atrophy and may be of interest as this is a symptom often associated with Huntington’s disease. Similar to tryptophan metabolism and the generation of associated neuromodulators, differences in dopamine and acetylcholine levels in Q175 brain tissue may contribute to altered motor coordination accompanying Huntington’s disease. Ultimately, a unique biochemical signature was identified in the plasma between Q175 and WT mice and may be of interest for future diagnostic and monitoring studies in patient cohorts.
Systems neuromedicine: Discovery of new pathobiologic networks and preclinical biomarkers
Howard J. Federoff, MD, PhD – Georgetown University
Alzheimer’s and Parkinson’s diseases (AD and PD) are the two most prevalent neurodegenerative diseases. In an effort to characterize potential etiopathogenic contributors in PD, the GPEX consortium undertook a meta-analysis of human midbrain tissue from PD patients. The data revealed that the master regulator of mitochondrial biogenesis, PGC-1а, and downstream respiratory complex subunit genes were coordinately down-regulated across the continuum of PD. We have now determined that PGC-1а is regulated epigenetically in PD brain tissue and have characterized a model system to study this mechanism. We are now pursuing PGC-1а as a drug target for PD. In another study, one involving older cognitively normal adults, we have discovered a set of plasma biomarkers that can predict phenoconversion to amnestic MCI or AD. These biomarkers represent metabolites, predominantly lipids and also exosomes. This work is being extended to additional cohorts and compels a secondary prevention trial in preclinical AD.
This work was supported by the NIA and DoD.
Nrf2 as an emerging HD therapeutic target
Larry C. Park, PhD – CHDI
In mammals, the transcription factor, nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a major regulator of cytoprotective and antioxidant gene expression. Under basal conditions, Nrf2 is negatively regulated by the protein Keap1, which binds and targets Nrf2 for ubiquitin-dependent degradation and represses Nrf2-dependent gene expression. In cells exposed to reactive chemicals or oxidative stress, surface exposed keap1 cysteine residues act as “stress sensors”, and release Nrf2, which enables it to translocate to the nucleus, bind to antioxidant response elements (ARE) of cytoprotective and antioxidant genes and activate their gene expression.
Evidence suggests that increased oxidative stress and a compromised antioxidant response in HD patients and HD animal models are potential pathogenic mechanisms driving disease progression. Antioxidants offer therapeutic potential for HD, however little benefits have been observed in clinical trials with “small molecule antioxidants”. Thus, CHDI focuses on developing brain penetrant and CNS active molecules capable of activating the innate cellular antioxidant response system via Nrf2-ARE activation as potential therapeutics for HD. We are applying structure-based drug design methods to develop new activators of Nrf2 by binding to keap1-Nrf2 docking site and disrupting the protein-protein interaction between Keap1 and Nrf2.
Identifying small molecule modulators of mutant huntingtin protein levels in HD patient-derived cells
George McAllister, PhD – BioFocus
Despite the identification of the pathogenic poly-CAG expansion in the huntingtin (Htt) gene as the cause of Huntington’s disease (HD) over 20 years ago, there remains no effective treatment for the disease. Clearly, reducing the levels of mutant HTT (mutHTT) is the best validated, most proximal approach to developing novel therapeutics. Whilst the molecular approaches described in the other talks in this session will offer the possibility to do this, the challenges of delivering such agents to the appropriate desired sites of action in patients are significant. A small molecule that reduces mutHTT levels would also have the potential benefits of the strategy but, with the correct bioavailability and brain penetration properties, would have a broader effect of lowering HTT in the periphery and CNS.
Numerous studies have been performed to try and identify molecules or genes which modulate the toxic effects or expression of mutant HTT (mutHTT). These studies have often been based around a single hypothesis (e.g., reducing aggregation or preventing caspase cleavage). Often, an exogenous promoter driving expression of a HTT fragment with a polyQ length well beyond a clinically relevant range is required to generate a sufficient assay signal suitable for reliable screening. This may have contributed to the lack of translatability of hit genes or molecules from one screen to another, and to higher in vivo models of HD.
Recent advances in sensitive and robust protein quantitation methodologies have allowed us to measure the expression of native mutHTT and total HTT proteins in a variety of patient-derived cell types. These advances allow higher throughput small molecule and RNAi screens targeting reduction of endogenous mutHTT levels in disease relevant CAG repeat length (~Q40-50) cell types to be developed. This presentation will detail how the assays perform in a number of patient-derived cell types (e.g., HD lymphoblasts, fibroblasts, and stem cells) including the results of a pilot screen in HD lymphoblasts of 7000 compounds (tested n=2) from the CHDI collection comprising of both hypothesis-based and diverse compounds that has demonstrated that: i) the HTRF assay employed is suitable for HTS (Z’ >0.3; S:B>2) and, ii) hit matter can be reliably detected and efficiently translated from single point to IC50 determinations.
Assay development to adapt this small molecule approach to HD stem cell models and to combine it with an RNAi screen will be discussed, alongside other important considerations, including, mechanism of action deconvolution approaches for such phenotypic screens, and selection of toxicity and counterscreening assays for an efficient HTS screening cascade.
Huntingtin lowering through selective inhibition of Hsp90 a/β
Presentation not available
Dean Stamos, PhD – Vertex Pharmaceuticals Incorporated
As the etiology of Huntington’s disease can be definitively traced back to the mutated gene, an approach towards disease modification through mHtt protein lowering is an appealing option. Towards this end we pursued a strategy of modulating the proteostatic network regulating cellular levels of mHtt via isoform selective inhibition of Hsp90. We demonstrated that inhibition of only the cytosolic isoforms of Hsp90 (Hsp90 α/β) is required for reduction of total Htt (mutant and wild-type) both in vitro and in vivo. This talk will describe the activity of centrally acting Hsp90 α/β inhibitors in both in vitro and in vivo models.
Widespread gene delivery to the nonhuman primate brain for the treatment of Huntington’s disease
Presentation not available
Lisa Stanek, PhD – Genzyme
Huntington disease (HD) is an autosomal dominant neurodegenerative disease caused by a CAG-trinucleotide repeat expansion in a coding exon of a single allele in the HTT locus. In HD, the resulting polyglutamine (polyQ) expansion confers a toxic gain-of-function to the mutant huntingtin protein (mHTT). Reduction of expression of mHTT using gene silencing by RNA interference (RNAi) may confer transformative disease modifying therapeutic approach for HD. Adeno associated vectors (AAV) provide an ideal delivery system for nucleic acid therapeutics and have the potential to allow for long lasting and continuous expression of these huntingtin lowering RNAi in the brain. Despite this promise, global delivery of AAV to the adult brain remains an elusive goal. Furthermore, the appropriate brain areas to target for achieving transformative therapeutic benefit in HD patients remain to be defined. Postmortem analyses of HD patient brains reveal extensive medium spiny neuronal loss in the striatum, in addition to loss of pyramidal neurons in the cerebral cortex and hippocampus. Recent studies in rodent models suggest that simultaneous targeting of striatum and cortex is more efficacious than targeting either individually. Thus, available evidence suggests that delivery of Htt-lowering therapeutics to both striatal and cortical regions may provide optimal therapeutic efficacy.
The current study demonstrate for the first time the successful use of an AAV targeting strategy that leads to viral transduction in key brain areas considered to be important for HD pathology. The study compared the efficiency of transduction of AAV1 and AAV2 vectors in the rhesus monkey brain following intra-striatal injection. Both vectors encoded green fluorescent protein (GFP) under control of a hybrid CMV enhancer/chicken beta-actin promoter. One month following injection, brains were analyzed for distribution of GFP-positive cells. We found that the AAV1 vector provided extensive delivery to the majority of the primate striatum (caudate and putmen), and additionally transduced large numbers of cells within the cerebral cortex (including frontal cortex, occipital cortex, and layer IV), thalamus, and hippocampus. We are currently evaluating the tropism of transduced cells within these regions. In summary, the data suggest that intrastriatal delivery maybe sufficient to for the delivery of nucleic acid-based therapeutics to multiple areas of the human brain relevant in HD.
Challenges in clinical translation for engineered zinc finger transcriptional repressors that selectively inhibit mutant huntingtin expression
Geoff Nichol, MB, ChB, MBA, FRACP – Sangamo BioSciences
Huntington’s disease (HD) is a fatal autosomal dominant neurodegenerative disease caused by CAG-trinucleotide repeat expansion in exon 1 of the huntingtin (Htt) gene. Multiple Htt-lowering strategies are being pursued as potential therapies for HD based on rodent studies showing that reduction of Htt levels lead to phenotypic improvement. Some of these methods down-regulate both wild type and mutant Htt, creating uncertainty because of the potential critical physiologic roles of wild type Htt. Others target mutant Htt based on single nucleotide polymorphisms (SNPs) and are applicable only to subpopulations of patients.
We sought to develop a therapeutic strategy that can selectively downregulate the mutant Htt allele expression and be potentially useful for most patients with HD. Engineered zinc-finger protein transcription factors (ZFP TFs) can be designed to bind almost any DNA sequence to regulate gene expression. By designing ZFPs to specifically recognize the CAG expansion, we showed that ZFPs can be engineered to minimally regulate the normal Htt alleles (CAG15-21) while driving approximately 90% repression of mutant Htt alleles (CAG40-69) in multiple HD fibroblasts and neurons. Repression of mutant Htt with ZFPs reversed multiple pathologic phenotypes exhibited by HD neurons. To test their in vivo efficacy, ZFPs were delivered using adeno-associated virus (AAV) vectors to the striatum of HD model mice. In R6/2 mice, the expanded allele-specific ZFPs significantly reduced the levels of mutant Htt mRNA without affecting normal Htt levels and increased expression levels of medium spiny neuron markers, suggesting ZFP-mediated protection of those cells. Significant improvements in clasping and motor defects were observed in ZFP-treated R6/2 mice. In Q175 mice, ZFPs prevented mutant Htt aggregation when delivered at 2 months of age and led to significant clearance of existing Htt aggregates when delivered at 6 months of age. These results support the further development of allele-specific ZFP repressors as an HD therapy.
Dose selection, route of administration, and other key challenges in clinical translation will be discussed.
Antisense oligonucleotide therapies for the treatment of Huntington’s disease
C. Frank Bennett, PhD – Isis Pharmaceuticals Inc.
Antisense oligonucleotides are chemically modified oligonucleotides that are designed to specifically bind to a targeted RNA through Watson-Crick base pairing. There are a variety of mechanisms which antisense oligonucleotides modulate RNA function after binding, including promoting the degradation of the RNA, modulating RNA processing and displacing regulatory proteins from interacting with the target RNA. Because antisense oligonucleotides target RNA, rather than protein, they can be used to modulate a broader range of therapeutic targets than can be approached with conventional small molecule or protein based drugs. Huntington’s disease is an attractive therapeutic opportunity for antisense technology, as the genetic basis for the disease is known and is not easily approachable with small molecule drugs. Single-stranded antisense oligonucleotides broadly distribute in CNS tissues following administration into the CSF, with commensurate modulation of gene expression in spinal cord and different brain regions. Spinal cord, cortical regions of the brain, hippocampus and Purkinje cells in the cerebellum accumulate the highest concentration of oligonucleotides following administration by lumbar puncture in rodents, non-human primates, dogs and pigs. Proof of concept studies in BACHD and YAC128 mice have been completed (Kordasiewicz et al., Neuron 74:1031-1044, 2012 and Stanek et al. J. Huntington’s Disease 2: 217-228, 2013) and supported advancing the program into drug discovery. After screening and characterizing several thousand ASOs for potency, biodistribution and pharmacokinetics, we have identified an antisense drug which we are advancing into development. We have completed toxicology studies to support clinical studies in patients and plan on starting the clinical studies later this year in Huntington’s disease patients. In addition to Huntington’s disease, we have completed early stage clinical studies in ALS and SMA demonstrating safety and tolerability of antisense drugs administered by intrathecal injection. The pharmacokinetic profile of antisense drugs in patients is similar to that observed in preclinical studies. These early clinical experiences in addition to the preclinical data support the continued development of antisense drugs for Huntington’s disease and other severe neurodegenerative diseases.
A strategy for the identification of translatable HTT-lowering biomarkers
Presentation not yet available
Douglas Macdonald, PhD – CHDI
Huntingtin protein (HTT) lowering is a key therapeutic strategy for Huntington’s disease (HD). Reducing the amount of the disease-causing expanded HTT protein in the brain of patients is predicted to slow the progression of the disease. Several approaches are being employed to lower HTT, including antisense oligonucleotides and siRNAs, as well as gene therapy approaches using viral delivery of miRNAs, shRNAs, and zinc-finger repressor proteins. To enable the advancement of such therapeutics to the clinic, translatable HTT-lowering pharmacodynamic and proximal biomarkers are being explored using preclinical models of HD. We seek to identify and validate outcome measures that indicate that the delivery of a HTT-lowering therapy does, in fact, lower the amount of HTT protein in the brains of HD patients.
Challenges and opportunities at NINDS: Lessons learned
Story Landis, PhD – Former Director, National Institute of Neurological Disorders and Stroke
The mission of NINDS is to seek fundamental knowledge and the brain and nervous system and to use that knowledge to reduce the burden of neurological disease. NINDS is responsible for a many diseases, both common and rare, and for funding research across the spectrum from basic studies to large clinical trials. Balancing scientific opportunities with investments across diseases and across the research spectrum presents an ongoing challenge, particularly with the present budget constraints. Starting in 2006, NINDS began to systematically assess large programs and initiatives and when appropriate close them down. New programs were designed to enhance the likelihood of harvesting fundamental discoveries for better understanding of disease and new therapeutics. Significant changes in clinical trial design and management, including analysis of the scientific rationale for the interventions being tested, increasing the likelihood that trials would not only test an intervention but also shed light on the disease itself. Attention to funding trends has increased NINDS’ ability to fulfill our mission. Specific examples will be chosen to highlight both the challenges and opportunities at NINDS.
Towards the understanding of Huntington’s disease through lipidomics
Gilbert Di Paolo, PhD – Columbia University Medical Center
Huntington’s disease (HD) is an autosomal dominant disorder with progressive striatal neurodegeneration, leading to characteristic motor and cognitive impairment. With a prevalence of about 5-10 cases per 100,000 people, HD can present at almost any age, with a life expectancy of 20 years after first symptoms. It is caused by expansion of the typical N-terminal polyglutamine stretch in huntingtin (Htt) protein. Normal Htt has been shown to have a diverse set of cellular roles, including participation in vesicular trafficking and interaction with lipid bilayers and signaling molecules. Furthermore, recent studies have suggested altered lipid metabolism in HD, especially in the endolysosomal system and associated lipids, like sterols and gangliosides, that traffic through these pathways. To query the pathophysiological role of mutant Htt interactions in HD, we undertook a lipidomic analysis to study five brain regions – prefrontal cortex, motor cortex, anterior and posterior thalamus, cerebellum – of both intermediate and late-stage HD human postmortem brain tissue with age-matched controls. We also studied the Q175 knock-in murine model at three symptomatically defined ages in both genders compared to age-matched controls. Cerebellum, cortex, corpus callosum, dorsal and ventral striatum, and hippocampus were investigated for the mice. Finally, we conducted a lipidomic analysis of plasma samples from control participants and HD patients in search of lipid biomarkers that can be diagnostic of HD. With our liquid chromatography/mass spectrometry based lipidomic methodology, we analyzed the abundance over 400 lipid species in over 30 subclasses, comprising sterols, glycerolipids, phospholipids, and sphingolipids. Some of these include low abundance bioactive lipids that have been demonstrated to have potent roles in brain function. In doing so, we anticipate uncovering novel roles of lipids, as pathogenic agents and/or simply as biomarkers of HD disease progression.
Biomarkers and biological insights from Huntington’s disease patient cerebrospinal fluid
Ed Wild, MD, PhD – University College London
Cerebrospinal fluid (CSF) allows the sampling of the central nervous system’s biochemical milieu safely, tolerably and ethically, offering the potential to study numerous aspects of Huntington’s disease directly in humans.
Focusing initially on two high-priority therapeutic strategies – lowering mutant huntingtin (mHTT) and modulation of the kynurenine pathway – we have begun a programme of CSF collection from premanifest expansion carriers, people with manifest HD and controls, under standardised conditions designed to minimise sources of error and maximise biological insight.
Using these CSF samples and a novel single-molecule counting immunoassay, we have detected and quantified mHTT in CSF. We show that its concentration independently predicts phenotypic features of HD and has the potential to act as a pharmacodynamic biomarker for huntingtin-lowering therapies.
Additionally we are using CSF to study several other questions of relevance to HD biology, biomarkers and therapeutic development, including neuroinflammation, neuronal proteins and the kynurenine pathway. Initial data will be presented on some of these analyses.
Brain atrophy, and mHTT-induced alteration of ependymal ciliary function, may alter the flow of CSF through the CNS, with potential implications for the spread of CSF-administered drugs and potential biomarker analytes. Using phase-contrast MRI, we have begun to study the physical dynamics of CSF in HD and some initial results will be presented.
Finally, tantalising details will be revealed of a major new international HD CSF collection initiative in collaboration with CHDI Foundation and academic partners.
Automated speech analysis for diagnosis in psychiatry
Guillermo Cecchi, PhD – T.J. Watson Research Center, IBM
The characterization of pre-manifest HD states and progression has been based on a number of cognitive, motor, and psychiatric assessments, involving a long and taxing battery of tests to be performed at the clinic, with active participation of clinicians. As a consequence, these assessments cannot be performed with high frequency, and require a population of predisposed patients. These limitations are shared with all other neurological and psychiatric conditions: according to the Centers for Disease Control and Prevention, 63.3 million psychiatric interviews are performed every year in the US. With very few exceptions, these interviews and diagnostic assessments are evaluated without any help of state-of-the-art computational methods.
We will discuss three pilot studies in which diagnostic and prognostic information is extracted automatically from the text of transcribed unstructured interviews. A study on short speech samples (~ 5 mins) of diagnosed psychotic schizophrenic and manic patients, along with matching controls, shows that graphs representing words transitions provide information yielding more than 90% accuracy in individual-to-group assignment. A second study, on psychoactive drug intake, shows that a statistical representation of semantic content of double-blind interviews (~ 20 mins) can discriminate between drug (ecstasy) and placebo sessions. A third study was designed to predict psychosis onset in youths at clinical high risk. Open-ended interviews (~40 mins) at baseline were followed by quarterly clinical assessments for up to 2.5 years to identify subjects who converted to psychosis. Using a combination of features that include discourse coherence and syntactic complexity, automated text analysis predicts with 100% accuracy the converted sub-cohort. Moreover, the speech features can be partially related to the baseline assessment psychometric scales, but the scales can only provide a predictive accuracy of 65%.
Finally, we will describe ongoing efforts on other psychiatric and neurological disorders (e.g. Parkinson’s disease), and how this approach can be applied specifically to the study of prodromal Huntington’s disease: what potential benefits it may yield, and how to complement speech-based studies with analytics on low-cost wearable sensors. The convergence of readily accessible measures and computational methods can provide highly relevant clinical information and constraints for disease modeling.
The role of precompetitive consortia, data sharing and regulatory science in catalyzing innovation for neurodegenerative diseases
Diane Stephenson, PhD – Critical Path Institute
Effective treatments for Huntington’s disease are associated with significant challenges that require collaboration, data sharing and innovation. The lack of success in development of disease modifying therapeutic candidates for neurodegenerative diseases has led to the recommendation of public private partnerships to tackle the challenges and share costs and risks amongst diverse stakeholders. The Coalition Against Major Diseases (CAMD) is one of eight consortia of the Critical Path Institute (C-Path), a non-profit organization formed in response to FDA’s Critical Path Initiative. Regulatory agencies in both US and Europe have identified quantitative disease models as a drug development tool platform to accelerate drug development. Quantitative pharmacometric modeling is an innovative approach that enables sponsors to analyze data from integrated multiple sources to accurately design prospective clinical trials. This presentation aims to highlight CAMD’s successful development for Alzheimer’s disease (AD) of the first drug-disease-trial model to receive regulatory endorsement.
Fundamental to the mission of CAMD is the sharing of non-competitive patient level data from legacy clinical trials, and transformation of those data into generalizable and applicable knowledge to advance therapies for Alzheimer’s and Parkinson’s diseases. A coalition of industry members, regulatory agencies, academic experts and patient groups collectively developed an analysis plan for a drug-disease-trial model in mild and moderate AD patients with the ADAS-Cog cognition measure as the primary outcome. Data standardization and database development was performed by a dedicated workgroup for the creation of C-Path Online Data Repository (CODR), which comprised de-identified patient level data from control arms of AD clinical trials. The drug-disease-trial model focused on mild and moderate cases of AD and is composed of a disease progression, a placebo effect, and a drug effect function. The model allows simulations of disease modifying activity, symptomatic activity or a combination of both mechanisms. The clinical trial simulation tool has been made publicly available and represents a milestone that serves to encourage the advancement of drug-disease-trial models and promises to increase the probability of success in future AD therapeutic trials. The applicability of a similar path for Huntington’s disease holds tremendous promise.
Pridopidine and laquinimod: Applying preclinical and clinical new insights for the treatment of HD
Michal Geva, PhD – Teva Pharmaceutical Industries Ltd
Teva is currently conducting clinical trials for Huntington’s disease (HD) with two compounds: pridopidine and laquinimod. In both cases, insights from preclinical and clinical studies have paved the way for investigations on their potential to benefit a wide range of symptoms and pathologies related to HD.
Pridopidine is an oral small molecule being developed for symptomatic treatment of HD. Pridopidine belongs to a class of dopaminergic stabilizers and activity is mainly attributed to its low affinity antagonistic interaction with the dopamine D2 receptor. Recently, we performed a series of preclinical studies that shed new light on pridopidine’s mechanism of action. These studies showed that pridopidine’s actions are not limited to the D2 receptor in the CNS suggesting potential for beneficial effects on both motor symptoms and disease progression in HD patients.
Laquinimod is a once-daily oral CNS-active immunomodulator being developed for the treatment of relapsing-remitting MS (RRMS), progressive MS and HD. The clinical profile of laquinimod in MS indicates beneficial effects on disability progression and brain atrophy that are not mediated by an effect on relapse rate. This implies that laquinimod has neuroprotective activity that is not of anti-inflammatory origin. Laquinimod has been shown to modulate pathways common to several neurodegenerative diseases, and we are currently investigating the molecular basis of these effects in greater detail.
In summary, pridopidine and laquinimod are two small molecules, acting by different mechanisms of action that have potential as novel treatments for HD. Clinical outcomes and preclinical studies, enhanced by in-depth understanding of the drug target and activity in the brain, should provide vital insights into potential new treatment paradigms for HD as well as other neurodegenerative diseases.
Preferential vulnerability of highly connected brain regions to structural connectivity loss in HD and identification of novel brain compensation in preclinical HD – new findings from Track-ON HD
Sarah J. Tabrizi, MD, PhD, FMedSci – University College London, on behalf of the Track-ON investigators
Understanding how neurodegeneration in HD affects brain connectivity is critical to understand the effects of new therapeutic targets. Recent evidence suggests that pathogenic misfolded HTT protein may spread trans-neuronally. We hypothesised that such pathological processes would lead to preferential structural connectivity loss of highly connected brain regions. We tested this hypothesis using diffusion tractography and graph theoretical analysis in premanifest and manifest HD participants versus controls from the TRACK-HD cohort. We found altered structural connectivity preferentially affecting these brain regions in both premanifest and manifest HD participants versus controls. These results show that HD results in a characteristic pattern of structural connectivity loss targeting highly connected brain regions with high network traffic and low clustering of neighboring regions; and yield new insights into understanding the loss of brain circuitry in HD with implications for the design of disease-modifying therapies.
Premanifest HD gene carriers maintain intact cognitive and motor performance for many years prior to clinical diagnosis despite substantial loss of volume in brain regions supporting task performance. Although an underlying mechanism of neuronal compensation has been previously hypothesized, concrete evidence linking behaviour, disease load and brain activity, is lacking. In Track-ON HD, we sought to identify these mechanisms by using resting state and task related functional MRI to measure brain activity in 90 premanifest HD gene carriers. We characterised disease load using structural MRI and studied how the relationship between performance and brain activity (or connectivity) changed as disease load increased. Consistent with compensation, we found that performance-related brain activity during a working memory challenge increased with disease load in parietal cortex, a region associated with task performance in healthy volunteers. Similarly functional coupling between right DLPFC and a left hemisphere network during the resting state that predicted cognitive performance was also modulated by disease load and suggested a compensatory effect in the right hemisphere. Similar patterns were absent in the left hemisphere and not associated with brain activity during motor tasks. Our findings thus provide evidence for compensation in premanifest HD and suggest a higher vulnerability of the left hemisphere to disease load.
Positron emission tomography in Huntington’s disease: New multi-modal approaches towards a definitive biomarker study
Marios Politis, MD, MSc, DIC, PhD – King’s College London
Over the past three decades, positron emission tomography (PET) has been powerful in providing insights into the molecular mechanisms underlying Huntington’s disease (HD). Early PET studies with the use of metabolic, dopaminergic and neuroinflammatory markers have been able to detect neurobiological alterations of glucose metabolism, dopamine type-1 and -2 receptors, and activation of microglia in both premanifest and manifest HD gene carriers. More recently, changes in cannabinoid type-1 receptors and phosphodiesterase 10A enzyme have also been characterised with in vivo PET in HD gene carriers. PET is an analytical imaging method with potential to give both structural and kinetic information, which could be significantly strengthened by using aid from a multi-modal imaging approach. For example, combination of PET with MRI-derived diffusion data allow connectivity-based functional analysis of PET signal that could be used for a pathway-based analysis within the neuropathological salient networks in HD gene carriers. Future goals should incorporate using PET imaging together with other functional and structural neuroimaging tools for better understanding the neurochemical and neurobiological alterations characterising the disease, and to assess the impact with regards to patient’s prognosis and treatment strategies. Such approaches will need robust methodology and analytical methods to allow sufficient quantification for a pathway-based phenotypic characterization along the clinical course of HD. This depth of imaging data together with adequate patient populations could then serve as the basis for a definite neuroimaging biomarker study for HD. In this respect, PETMARK-HD, the first multi-modal and multi-target neuroimaging programme that aims to build a cortical-striatal signature of pharmacodynamic biomarkers across a broad range of HD for significantly advancing decision-making in patient management and therapeutic development will be presented.
Huntington disease: Clinical trials 2014
Ray Dorsey, MD – University of Rochester Medical Center
Disclosures: I have received research funding from Auspex Pharmaceuticals, Huntington Study Group, and Prana Biotechnology for efforts related to Huntington disease. The Huntington Study Group (which I chair) helped conduct the 2CARE, CREST-E, Reach2HD, and First-HD clinical trials.
Clinical trial activity in Huntington disease (HD) has never been greater. The past year saw the conclusion of several important trials. The disappointing news was the two largest clinical trials in Huntington disease ever – 2CARE (a randomized controlled trial of coenzyme Q10) and CREST-E (a randomized controlled trial of creatine) – both concluded prematurely due to futility. The NIH-funded studies both enrolled over 500 participants and followed participants for up to five years. While the studies demonstrate the ability to conduct large scale and long duration studies in HD, they highlight the clear need for better, objective, sensitive markers of disease progression. Such markers, many of which have been identified through TRACK-HD, need to be evaluated in clinical trials so early stage trials can determine whether interventions are likely to have benefit before large and expensive trials commence.
The past year also provided hopeful signs of potentially beneficial therapies for HD. Studies aimed at the cognitive and motor effects of HD demonstrated at least the potential for benefit. Prana Biotechnology completed a phase II study of PBT2, a metal protein attenuating compound that may decrease oligomerization of mutant huntingtin. The study (Reach2HD) demonstrated that the drug is generally safe and well tolerated and demonstrated a signal of benefit on a measure of executive function (Trail Making Test Part B) that was consistent with a previous trial of the drug in Alzheimer disease and that requires confirmation in a future trial. Raptor Pharmaceuticals also released 18-month results of a double-blind trial of cysteamine, which may improve mitochondrial function and reduce polyglutamine aggregation, in HD. While the drug did not demonstrate benefit on the primary outcome of the total motor score, a sub-group analysis suggested that the drug may have motor benefit on those not taking tetrabenazine. Finally, Auspex Pharmaceuticals released very promising results from its clinical trial of deuterated tetrabenazine (SD-809) demonstrating improvement on chorea, total motor score, clinical global impression, and quality of life. The results should lay the foundation for the second FDA-approved treatment for HD. The coming year promises more trials aimed at making HD an increasingly treatable condition.
Randomized controlled trials (RCT’s) in Huntington’s disease in 2015: Unmet needs, challenges and hopes
G. Bernhard Landwehrmeyer, MD, FRCP – University of Ulm & CHDI
This year, for the first time ever, a therapeutic approach specifically designed for HD will be put to clinical test; Isis Pharmaceuticals will begin investigating the safety, tolerability and pharmacokinetics of multiple ascending doses of a non-allele selective, intrathecally-administered antisense oligonucleotide in early stages of HD. Although not designed to test efficacy, it is hoped that this RCT will identify pharmacodynamic markers for huntingtin gene silencing. Setting appropriate expectations in the HD community will be an important undertaking during this trial.
Given that it will take time for gene-silencing therapies to mature to implementable therapeutic options for HD, initiatives to ameliorate disease signs and symptoms are timely and highly relevant. Pfizer is conducting a Phase 2A proof-of-concept RCT to study the safety and efficacy of a selective phosphodiesterase (PDE)-10A inhibitor, PF-02545920. Preclinical studies suggest that PDE10A inhibition partially restores function to HD-deranged cortico-striatal brain circuitry. Two dose levels will be studied over 26 weeks in around 260 participants to explore the efficacy on motor function (primary endpoint) and signs thought to reflect striatal dysfunction. Also, later this year a single-center Phase 2A RCT with a 28-day exposure to PF-02545920 conducted in Paris (PI: Alexandra Duerr) will be reported.
LEGATO-HD (Teva, Phase 2) is investigating the safety and efficacy of three dose levels of laquinimod, an immunomodulator with actions on CNS-resident immunocompetent cells, possibly through the NF-ΚB pathway. The RCT with 12-month exposure in about 400 participants will explore the potential to ameliorate brain atrophy (measured by MRI) and will use motor function (UHDRS-TMS) as primary endpoint. The UHDRS-TMS also serves as primary endpoint in the Pride-HD trial (Teva, Phase 2, dose-finding), which is evaluating the safety and efficacy of pridopidine at 4 dose levels (90 – 225 mg/d); pridopidine is a dopamine modulator with activity on sigma-1 receptors. This 6-month RCT with around 400 participants will address whether dosages of pridopidine > 90 mg/d are well tolerated, improve the motor features of HD by > 3TMS points, lead to cognitive and behavioral ameliorations and result in real-life benefit for patients.
The RCTs conducted in 2015 are powered to yield conclusive results. However, their relatively large size (cumulatively > 1000 HD patients) and their contemporaneous execution present challenges fostering global collaboration and coordination. Overall, the RTCs of 2015 promise to bring the HD community closer to identifying therapeutics that really work.