Volume 15

HD Insights Volume 15 (PDF)

To read a non-PDF version of HD Insights Vol. 15, click here.

Finding balance in HD: The role of PIAS1 in protein homeostasis


Figure. The biochemistry in our brains is in a constant balance. In neurodegenerative disease, the scales often tilt toward a dysfunctional state. By restoring the fine balance of levels of PIAS1 in a mouse model of HD, we showed not only improvements in behavioral deficits, but a restoration of balance in several pathways known to be out of balance in HD. Decreasing the burden of PIAS1 on the cell appears to cause a shift in cellular homeostasis toward a protective state. This study suggests that PIAS1 and other E3 SUMO ligases may be key to tipping the balance between normal protein homeostasis and disease processes that cause neurodegeneration.

By: Joseph Ochaba, PhD
There are currently no medications or treatments to alter the devastating course of HD. Although some medications to ameliorate HD symptoms exist, they are often of limited effectiveness;1 therefore, there is a great need to develop treatments and discover targets to effectively alter the course of HD. As in many other neurodegenerative diseases, the underlying pathology of HD involves the decline or loss of protein quality control networks, homeostasis, and the consequent accumulation of highly insoluble protein complexes that in the case of HD contain modified and misfolded mHTT protein and other post-translationally modified proteins.

Previous studies in the lab demonstrated that the enzyme PIAS1 (an E3 SUMO-protein ligase) alters mHTT accumulation and SUMO modification of HTT in cells.2 In collaboration with Dr. Beverly Davidson’s group at the Children’s Hospital of Philadelphia, our lab recently investigated the role of PIAS1 as a potential new therapeutic target for HD in an animal model of the disease.
To examine its role in HD pathology, PIAS1 expression levels were modulated in the striatum of a rapidly progressing HD mouse model, R6/2.3 Using miRNA to knock down PIAS1 expression in the striatum, we found significant improvements in HD-associated phenotypes in a battery of motor and neuromuscular tasks; reduced pathogenic accumulation of insoluble mHTT; and improved longevity of the mice, with reduced levels of PIAS1 compared to controls.

Strikingly, reduced PIAS1 levels ameliorated neuroinflammatory disease – associated increases in apparent microglial accumulation and dysregulation of relevant proinflammatory cytokines. Conversely, overexpression of PIAS1 exacerbated disease phenotypes and the accumulation/aggregation profile. While the exact contribution of PIAS1 in HD remains unclear, we have demonstrated that this particular enzyme may provide a new target for RNAi-mediated suppression to treat several aspects of HD, including reversing protein aggregation; increasing synapses; and reducing inflammation – all of which contribute to maintaining a delicate biological balance – while also slowing or perhaps reversing behavioral decline.

While aberrant neuronal signaling, inflammation, energy production, and gene expression underlie the molecular basis of HD, a delicate balance of functional properties of the proteome ultimately dictates cell function.4,5 Under normal conditions, proteome integrity is maintained by the proteostasis network. In HD, chronic expression of expanded polyglutamine peptides results in an age-dependent collapse of this balance as evidenced by increased aggregation and mislocalization and dysfunction of stable proteins.6 Because many of these networks may be potential therapeutic targets, our current work aims to investigate more longitudinal approaches by assessing the effects of PIAS1 modulation and mHTT accumulation/aggregation dynamics in long-term mouse models of the disease, in addition to clinically relevant human patient – derived induced pluripotent stem cell neuronal subtypes, in order to fully understand the contribution of PIAS1 to HD and evaluate its potential as a clinical target. The cellular environment plays a significant role in determining whether disease proteins are converted into toxic or benign forms, and for this reason, understanding the role that PIAS1 plays pre- or post-symptomatically will be important moving forward.

Our results strengthen the link between accumulation of insoluble protein complexes and HD pathogenesis, and suggest that PIAS1 protein is a potential new target for future therapies in HD. Together, the fundamental properties identified here may also broadly impact other diseases, suggesting that regulating multifunctional proteins such as PIAS1 may be one key to tipping the balance between normal protein homeostasis and disease processes that cause neurodegeneration.


  1. Frank S. Treatment of Huntington’s disease. Neurotherapeutics. 2014 Jan;11(1):153-60. doi: 10.1007/s13311-013-0244-z.
  2. O’Rourke JG, Gareau JR, Ochaba J, et al. SUMO-2 and PIAS1 modulate insoluble mutant huntingtin protein accumulation. Cell Rep. 2013 Jul 25;4(2):362-75. doi: 10.1016/j.celrep.2013.06.034. Epub 2013 Jul 18
  3. Ochaba J, Monteys AM, O’Rourke JG, et al. PIAS1 regulates mutant huntingtin accumulation and Huntington’s disease-associated phenotypes in vivo. Neuron. 2016 May 4;90(3):507-20. doi: 10.1016/j.neuron.2016.03.016. Epub 2016 Apr 14
  4. Tsvetkov AS, Arrasate M, Barmada S, et al. Proteostasis of polyglutamine varies among neurons and predicts neurodegeneration. Nat Chem Biol. 2013 Sep;9(9):586-92. doi: 10.1038/nchembio.1308. Epub 2013 Jul 21
  5. Reiner A, Dragatsis I, Dietrich P. Genetics and neuropathology of Huntington’s disease. Int Rev Neurobiol. 2011; 98: 325–372. doi:  10.1016/B978-0-12-381328-2.00014-6
  6. Margulis J, Finkbeiner S. Proteostasis in striatal cells and selective neurodegeneration in Huntington’s disease. Front Cell Neurosci. 2014 Aug 7;8:218. doi: 10.3389/fncel.2014.00218. eCollection 2014.

Meet the Company: WAVE Life Sciences

Name: WAVE Life Sciences
Stock symbol: WVE
Share price as of 10/9/16: $30.27
Market capitalization: $574 million
U.S. Headquarters: Cambridge, MA


Brenda Jeglinski serves as the Director of Clinical Operations at WAVE. She enjoys spending her free time with her husband and children.

Wendy Erler, MBA is the Vice President of Patient Advocacy and Market Insights at WAVE. When she is not working to bring precision medicines to patients, she enjoys paddleboarding and spending time with her husband and their three children.

Wendy Erler, MBA is the Vice President of Patient Advocacy and Market Insights at WAVE. When she is not working to bring precision medicines to patients, she enjoys paddleboarding and spending time with her husband and their three children.


Michael Panzara, MD, MPH is the Franchise Lead for Neurology at WAVE. When he is not thinking about precision medicines for HD, he enjoys spending time at home with his family.

Precision Medicine for HD
WAVE Life Sciences, a preclinical biopharmaceutical company publicly traded since 2015, utilizes their proprietary platform to synthesize stereopure nucleic acid therapies for currently untreatable genetic diseases. HD Insights spoke with Brenda Jeglinski, Director of Clinical Operations, Wendy Erler, Vice President of Patient Advocacy and Market Insights, and Michael Panzara, Franchise Leader for Neurology, about the company’s work in HD. The following is an edited transcript of the conversation.

HD INSIGHTS: Thank you all for joining us today. Please tell us about WAVE Life Sciences.

JEGLINSKI: We are a small company, just starting our first clinical trials. We are currently working with investigators to develop our clinical trials, and identify where and when we can begin the first human dosing with our compounds.

ERLER: One of the exciting things about WAVE is that we have a number of people who have come into the company with past experience working in oligonucleotides, and that has really informed our HD program in particular.

HD INSIGHTS: How did WAVE first become interested in HD?

PANZARA: One of the unique aspects of our oligonucleotide platform is that we are able to control properties of each oligonucleotide, including specificity. This enables an allele-specific approach when targeting genetic diseases, making the mutation in HD an ideal target. In addition, WAVE is building a neurology franchise upon this platform. Neurological diseases are an area of high unmet need and our primary focus at WAVE. Combining our platform with our focus on this area of high unmet need, HD seemed liked the ideal place for us to begin to develop the next generation of therapeutics.

HD INSIGHTS: You mentioned that your approach is allele-specific. Other companies are developing non – allele-specific compounds. Can you talk about the possible relative advantages of allele specificity?

PANZARA: Healthy huntingtin protein (HTT) has many essential functions in the nervous system, while the presence of mHTT leads to neurodegeneration, so we thought that if we could develop an approach that targeted the gene product, the transcript of the mHTT allele specifically, while leaving the transcript for the healthy protein intact, we could potentially increase the benefits of treatment while minimizing risks. One of the strengths of controlling the stereochemistry of nucleic acid synthesis is that it allows us to specifically enhance and adjust properties of the nucleic acid, such as its stability, its activity, its immunogenicity, and most importantly, its specificity, which enables an allele-specific approach to treatment of the disease.

HD INSIGHTS: Can you talk about the preclinical evidence, and the importance of allele specificity?

PANZARA: The literature suggests that HTT has many important functions in preservation of neuronal health in the central nervous system, which is what prompted us to explore the potential to target mHTT in a selective way.1-4 By controlling stereochemistry, we have been able to design an antisense oligonucleotide that appears to discriminate between HTT and mHTT. We have done experiments in fibroblasts from HD patients known to have specific single nucleotide polymorphisms (SNPs) associated with their HD mutations. We have designed our oligonucleotides to target those SNPs, and demonstrated in this system that mHTT can be reduced significantly, while leaving healthy wild-type HTT relatively intact (WAVE preclinical data). Again, the overarching goal was to create a very specific effect on the detrimental protein, while leaving the wild-type protein intact, attempting to maintain normal neuronal function.

ERLER: To date, nucleic acid therapies have comprised complex mixtures of hundreds of thousands of chemical entities called stereoisomers. Some of those stereoisomers have therapeutic effects, while some are less beneficial, or have an unknown impact, and could contribute to undesirable side effects. With WAVE’s novel chemistry platform, we eliminate those complex mixtures, giving us control over the pharmacology by creating stereopure compounds. This rational, very specific design is what gives all the attributes just described specific to our HD candidates, but also allows us to use our oligonucleotides in other ways, such as exon skipping.

HD INSIGHTS: Tell us about your regulatory status.

PANZARA: We intend to file two INDs before year’s end, and we have been granted orphan drug designation in the USA. This should enable us to initiate studies in the early part of 2017 that focus on two distinct patient populations.

HD INSIGHTS: Can you tell us about the patient populations that you are looking to enroll in your first clinical trials?

PANZARA: Our compounds are developed to target the two most common SNPs associated with the mHTT allele which encompasses nearly two-thirds of the HD population. In addition, we are looking to enroll patients over 25 years old with early manifest HD.

ERLER: This is a really good opportunity to explain why there are two INDs being filed, since so many in the community have had exposure to other programs, specifically Ionis’s (see HD Insights, Vol. 13). Our planned INDs are, in fact, for two separate drug candidates for HD patients specifically targeted to two distinct SNPs (SNP 1 or SNP 2), so that means patients who are screened for these studies, will have a blood test to determine if they are eligible for SNP 1 or SNP 2 (see Meet the Compounds, p. 19). We plan to run both studies in parallel at the same trial centers.

PANZARA: In addition, an individual who does not want to know their CAG repeat number or their full genotyping can still participate in the study. The screening test would focus only on study eligibility, and the presence of either SNP 1 or SNP 2. From there, they would then have the opportunity to enroll, assuming they meet other inclusion and exclusion criteria.

JEGLINSKI: Another key factor is that because there is SNP 1 versus SNP 2, there are two different programs, but they are identical studies. There is no benefit or anything more enticing in one study versus the other.

HD INSIGHTS: It sounds as if WAVE is focusing on precision medicine, or personalized medicine – not only just focusing on a particular condition, but focusing on particular subpopulations within that condition.

PANZARA: Exactly. We see this as an important step towards precision medicine, designing the most appropriate drug for a given patient. We also see this as the start of an important part in the history of WAVE Life Sciences. These will be our first two clinical studies in precision medicine, but I think it epitomizes our approach to diseases with high unmet need: focusing on the most appropriate drug for a given patient.

HD INSIGHTS: Can you say when these precision medicine treatments will be investigated in clinical trials?

PANZARA: Our intention for HD is open both trials in the first part of 2017. These will be phase 1 safety studies.

HD INSIGHTS: This is WAVE’s first involvement in HD. Can you tell us a little bit about your impressions of the HD community? Any surprises or disappointments?

ERLER: I feel completely privileged and honored to have engaged with the HD community. It has been one of the most gratifying personal experiences of my career, because the community is incredibly open and warm, and very, very interested in sharing their stories so that we as an organization can better understand the true experience of living with HD, not just as a patient, but as a caregiver, or a spouse, son or daughter of someone who is living with HD. It has completely encouraged me to fight on behalf of these families, because I have just been so incredibly impressed with their fortitude and tenacity, and universal positive attitudes in light of their burden. At WAVE, we have been fortunate to have HD community members, patients and care givers, come to our office to meet with our team and share their stories and we have also been able to have WAVE employees participate in several HD fund raisers.
So while I knew this was a devastating disease, I was definitely surprised at just the sheer will and force these families have, and how positive they are, and how everybody without question comments about wanting to get involved with our clinical trials, not to help themselves, but to help future generations.

PANZARA: The only thing I would add is that because I am relatively new to WAVE and to this particular therapeutic area from a drug development standpoint, I have been extremely impressed by the sense of collaboration and purpose of the HD community. Everyone is universally focused on doing whatever they can for patients with this disease.

HD INSIGHTS: Thank you all very much for your efforts and for WAVE’s interest in developing precision treatments for HD. We wish you all the best, and great success in the future.

1. Dragatsis I, Levine MS, Zeitlin S. Inactivation of Hdh in the brain and testis results in progressive neurodegeneration and sterility in mice. Nat Genet. 2000;26(3):300-306.
2. Leavitt BR, van Raamsdonk JM, Shehadeh J, et al. Wild-type huntingtin protects neurons from excitotoxicity. J Neurochem. 2006;96(4):1121-1129.
3. Rigamonti D, Sipione S, Goffredo D, Zuccato C, Fossale E, Cattaneo E. Huntingtin’s neuroprotective activity occurs via inhibition of procaspase-9 processing. J Biol Chem. 2001;276(18):14545-14548.
4. Zhang Y, Leavitt BR, van Raamsdonk JM, et al. Huntingtin inhibits caspase-3 activation. EMBO J. 2006;25(24):5896-5906.

Meet the Compounds: WVE-120101 and WVE-120102

Image source: Robinson R. RNAi Therapeutics: How Likely, How Soon? PLoS Biol. 2004 Jan;2(1):E28. Epub 2004 Jan 20. DOI: 10.1371/journal.pbio.0020028. Published under a Creative Commons 2.5 License.

Image source: Robinson R. RNAi Therapeutics: How Likely, How Soon? PLoS Biol. 2004 Jan;2(1):E28. Epub 2004 Jan 20. DOI: 10.1371/journal.pbio.0020028. Published under a Creative Commons 2.5 License.

By: Meredith A. Achey, BM
Manufacturer: WAVE Life Sciences
Molecular formula: Stereopure antisense oligonucleotide (ASO) targeting single nucleotide polymorphisms (SNPs).
Mechanism of action: WVE-120101 and WVE-120102 act by selectively binding mHTT mRNA, thereby selectively inhibiting production of mHTT. WAVE Life Sciences has developed a strategy to synthesize stereopure nucleotide-based therapies that may improve their efficacy and safety.1

Nucleotide-based gene silencing therapies such as RNA interference (RNAi) and antisense oligonucleotides (ASOs) represent some of the most promising potential therapies for genetic diseases such as HD. However, methods for their synthesis developed to date produce mixtures of stereoisomers, some of which are therapeutic, and others that may be less effective or potentially detrimental.1,2 WAVE Life Sciences has developed a propriety technology for the synthesis of stereopure nucleic acid therapeutics3-5 with the potential to improve therapeutic efficacy and reduce harmful effects.6
The company hopes to develop stereopure nucleic acid therapies for a variety of genetic diseases, including central nervous system disease such as HD, and a number of genetic disorders that affect other organ systems.7

WAVE’s most advanced HD programs currently encompass two compounds that target different single nucleotide polymorphisms (SNPs) common to the mutant allele. The company plans to file investigational new drug applications for both of these compounds this year, and has received orphan drug designation in the US for its lead candidate, WVE-120101.8 These compounds target the two most common SNPs associated with mHTT.9 Current efforts by Ionis in the first human trial of a gene-silencing nucleotide-based therapy do not target mHTT selectively (see HD Insights, Vol. 13), although preclinical data have not suggested a significant decrease in efficacy nor increase in potential harm from a non-selective approach.10 However, interest in more selective approaches has continued because the possibility for off-target effects with non-selective silencing remains problematic.11-15

Pfister and colleagues9 reported that they have been able to develop small interfering RNAs (siRNAs) that target specific SNPs to treat approximately 75% of individuals with HD. In 2015, targeting approaches were further refined with the discovery that targeting three common haplotypes could enable selective silencing of the HD gene in approximately 80% of patients.13 The use of stereopure synthesis to enhance the delivery and efficacy of these highly targeted compounds may further refine ongoing efforts to develop an effective and safe gene-silencing therapy for HD.

Table. Selected studies of allele-specific gene-silencing therapies

Study Year Type of therapy Most promising target SNP(s) Summary
Skotte NH et al.16 2014 ASO rs7685686_A Allele-specific, high affinity ASOs targeting different SNPs associated with HD could together offer allele-selective silencing to approximately 50% of patients, and non-selective silencing to the remainder.
Drouet et al.12 2014 shRNA rs363125, rs362331, rs2276881, rs362307 shRNA delivered with a lentiviral vector to cellular and animal models showed in vitro and in vivo silencing of mHTT.
Yu D et al.17 2012 ss-siRNA Targets CAG repeat ss-siRNA targeting expanded CAG repeats led to selective silencing of mHTT expression in an HD mouse model.
Abbreviations: ASO: Antisense oligonucleotide; shRNA: small hairpin RNA; ss-siRNA: single-stranded small interfering RNA; SNP: single nucleotide polymorphism

1. Wild EJ, Tabrizi SJ. Targets for future clinical trials in Huntington’s disease: What’s in the pipeline? Mov Disord. 2014 Sep 15;29(11):1434-45. doi: 10.1002/mds.26007. Epub 2014 Aug 25.
2. De Mesmaeker A, Altmann K-H, Waldner A, Wendeborn S. Backbone modifications in oligonucleotides and peptide nucleic acid systems. Curr. Opin. Struct. Biol. 1995;5(3):343-355.
3. Butler D, Iwamoto N, Meena M, et al. Chiral control. Google Patents; 2015.
4. Verdine GL, Meena M, Iwamoto N. Novel nucleic acid prodrugs and methods of use thereof. Google Patents; 2012.
5. Verdine GL, Meena M, Iwamoto N, Butler DCD. Methods for the synthesis of functionalized nucleic acids. Google Patents; 2014.
6. Wave Life Sciences. Wave Life Sciences – Platform. [Website]. 2016; www.wavelifesciences.com/platform. Accessed August 19, 2016.
7. Wave Life Sciences. Wave Life Science – Pipeline. 2016; www.wavelifesciences.com/pipeline. Accessed August 19, 2016.
8. WAVE Life Sciences receives orphan drug designation from FDA for its lead candidate designed to treat Huntington’s disease [press release]. June 21, 2016.
9. Pfister EL, Kennington L, Straubhaar J, et al. Five siRNAs targeting three SNPs may provide therapy for three-quarters of Huntington’s disease patients. Curr. Biol. 2009;19(9):774-778.
10. Kordasiewicz Holly B, Stanek Lisa M, Wancewicz Edward V, et al. Sustained therapeutic reversal of Huntington’s disease by transient repression of Huntingtin synthesis. Neuron. 2012 Jun 21;74(6):1031-44. doi: 10.1016/j.neuron.2012.05.009.
11. Carroll JB, Warby SC, Southwell AL, et al. Potent and selective antisense oligonucleotides targeting single-nucleotide polymorphisms in the Huntington disease gene / Allele-specific silencing of mutant huntingtin. Mol Ther. 2011 Dec;19(12):2178-85. doi: 10.1038/mt.2011.201. Epub 2011 Oct 4.
12. Drouet V, Ruiz M, Zala D, et al. Allele-specific silencing of mutant huntingtin in rodent brain and human stem cells. PLoS One. 2014 Jun 13;9(6):e99341.
13. Kay C, Collins JA, Skotte NH, et al. Huntingtin haplotypes provide prioritized target panels for allele-specific silencing in Huntington disease patients of European ancestry. Mol Ther. 2015 Nov;23(11):1759-71.
14. Miniarikova J, Zanella I, Huseinovic A, et al. Design, characterization, and lead selection of therapeutic mirnas targeting huntingtin for development of gene therapy for Huntington’s disease. Mol Ther Nucleic Acids. 2016 Mar 22;5:e297.
15. Pfister EL, Kennington L, Straubhaar J, et al. Five siRNAs targeting three SNPs may provide therapy for three-quarters of Huntington’s disease patients. Curr Biol. 2009 May 12;19(9):774-8.
16. Skotte NH, Southwell AL, Østergaard ME, et al. Allele-specific suppression of mutant huntingtin using antisense oligonucleotides: providing a therapeutic option for all Huntington disease patients. PLoS One. 2014 Sep 10;9(9):e107434.
17. Yu D, Pendergraff H, Liu J, et al. Single-stranded rnas use rnai to potently and allele-selectively inhibit mutant huntingtin expression. Cell. 2012 Aug 31;150(5):895-908.

Highlights from the Journal of Huntington’s Disease

jhdInduced pluripotent stem cells in HD research
By: Kimberly Kegel-Gleason, PhD
Original article: Tousley A, Kegel-Gleason KB. Induced Pluripotent Stem Cells in Huntington’s Disease Research: Progress and Opportunity. J Huntingtons Dis. 2016 Jun 28;5(2):99-131. doi: 10.3233/JHD-160199.

Although many cell types are affected in HD, the impact of the disease on CNS neurons is remarkable. Neurons of the cortex and striatum degenerate and eventually die, causing the majority of HD symptoms. Until recently, it has been difficult to study human CNS neurons because of ethical considerations – it is not ethical to perform a biopsy on human patients to obtain brain cells for research. Embryonic stem cells (ESCs) are pluripotent, meaning that they have the ability to become neurons; however, the use of ESCs to obtain neurons is also fraught with ethical challenges, including the destruction of an embryo. Enter induced pluripotent stem cells (iPSCs). Skin or blood cells from controls and HD patients can be made into iPSCs by the introduction of just a few factors. iPSCs are very similar to ESCs and can be differentiated to resemble CNS neurons or other CNS cell types in order to study disease mechanisms, and to screen compounds that might be developed into new therapies.

A major advantage to iPSCs is that normal and mutant proteins are expressed at endogenous levels just as they are in the human patient; furthermore, the effects of varied genetic backgrounds on the behavior of the mutant protein can be assessed. Studies with iPSCs from patients with neurodegenerative diseases other than HD have provided new insights previously not found using animal models. For instance, using three-dimensional cultures of CNS neurons from iPSCs from human Alzheimer disease (AD) patients, intracellular tangles, which are major feature of AD, were observed.1 Intracellular tangles had never been recapitulated in mouse models of AD, and the results pointed to a particular protein only found in humans as a major target of pathology.

As with research in other neurodegenerative diseases, iPSCs from controls and HD patients have been in development to uncover previously unknown human-specific pathological mechanisms, to validate phenotypes identified in animal models, and for compound screening. In our review,2 we characterize the state of the HD iPSC field. We describe the current inventory of cells available to HD researchers, many of which cells are freely available. We also highlight changes that have been identified in HD cells compared to controls, in pathways, individual gene changes, functional phenotypes, and the role of stress and aging. Furthermore, we compare results obtained with various neuronal differentiation protocols.

Table: Summary of major progress and opportunities for expanded research using HD IPSCs


Progress Opportunities
Numerous HD iPSCs created Increase the number of HD and control lines used within each study
A few genetically corrected, isogenic iPSCs created Increase number of genetically corrected, isogenic iPSCs created and available (CRISPR/Cas9)
Several studies on neuronal cultures using diverse differentiation protocols Use of reproducible protocols for comparison of results across laboratories
Stress-induced phenotypes identified Expand the phenotypes identified in the absence of stress
SiRNAs and miRNAs targeting alleles with SNPs, Zinc Finger Proteins Develop additional allele-specific reagents and tools to target mHTT
Two studies with iPSC astrocytes Studies with iPSC glia (astrocytes, oligodendrocytes, microglia)
Co-culturing, 3-D cultures, and organoids
Artificial aging

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We also note the pervasive use of stress to unveil functional phenotypes in HD cells. Because stress exacerbates HD symptoms in patients, this may reflect important disease mechanisms. One argument in favor of this approach is that iPSC induced neurons are very immature compared to those in the brain of an adult with HD, so stress might mimic aging to enhance a phenotype. However, more time spent investigating what may be more subtle phenotypes in the absence of stress may lead to a better understanding of underlying pathology that leaves a cell vulnerable to stress and eventually triggers disease.

Although much progress has been made, culturing and differentiating iPSCs is still extremely expensive, time consuming and difficult, thus limiting the number of investigators who can take advantage of this valuable resource. We hope this review will enable those new to the iPSC field to consider and control the inherent problems with iPSC lines, and so enable reproducible research across the field.

One major limitation we found for interpreting data across the HD field is the relative paucity of cell lines used – many times, reports include data from just one cell line. In order to increase the reproducibility of research across the field, we suggest that results from at least three HD cell lines from three individual patients and three cell lines from three individual controls be used for robust phenotypes (six lines total). For more subtle phenotypes it may be necessary to use many more cell lines. For comparison, 10–12 control cell lines are currently being used by investigators in other fields.3 Alternatively, a combination of control cell lines (cell lines from unaffected individuals), and genetically corrected cell lines (using homologous recombination or CRISPR), and use of effective mHTT-lowering reagents such as siRNAs, miRNAs or zinc finger proteins in HD lines could be used. We note that data from genetically corrected cell lines should be interpreted with caution because the cell lines undergo several rounds of selective pressure during their generation that could alter a particular phenotype.

Our review of the field identifies areas of opportunity for which additional research would be of great value. For instance, very few studies used other brain cell types that can be differentiated from iPSCs such as astrocytes and oligodendrocytes, which may also impact HD pathology. The field should welcome more studies using iPSC-derived glial cells.

1. Choi SH, Kim YH, Hebisch M, et al. A three-dimensional human neural cell culture model of Alzheimer’s disease. Nature. 2014;515(7526):274-278.
2. Tousley A, Kegel-Gleason KB. Induced Pluripotent Stem Cells in Huntington’s Disease Research: Progress and Opportunity. J Huntington’s dis. 2016;5(2):99-131.
3. Boulting GL, Kiskinis E, Croft GF, et al. A functionally characterized test set of human induced pluripotent stem cells. Nat Biotechnol. 2011;29(3):279-286.

Career Opportunity: Vice President, Global Specialty Development, NDD, Teva

teva_cns_logoVice President, Global Specialty Development, NDD

The Role

The Vice President, Global Clinical Development, NDD will report directly to the Vice President, Global Head, NDD/MDS & Clinical Research Innovation within the global R&D function, overseeing the clinical development of Huntington’s Disease. This is a critical role within the company, having a significant impact in defining the clinical development strategy at a high level.

The outstanding individual sought will need to be of the highest caliber medically and scientifically, with exceptional leadership capacity and interpersonal skills and the ability to work in a dynamic and truly global company that is growing rapidly. This means flexibility, taking initiative, thinking “on the fly”; a desire to be very hands-on, decisive, and self-assured are critical.

More specifically, the Vice President will be responsible for providing scientific/medical leadership and support for Huntington’s disease products now going into phase III development programs as well as looking to develop the early pipeline. There are several regulatory filings on the horizon; this individual will provide leadership and guidance throughout the process. With the addition of several new DRUG/COMPOUNDS to the NDD pipeline, the visibility of the portfolio has been elevated and the new Vice President will be a very important part of the company’s near and long-term future.

Close collaboration with Key Opinion Leaders in the Huntington’s disease market and with Teva’s Commercial and Medical Affairs groups will be critical. The new Vice President will have significant leadership responsibilities, s/he will have be an essential member of the senior management team to develop the overall strategy for the franchise and provide scientific leadership to motivate, retain and develop the group.

The clinical development department is highly team-oriented. Trust and respect is paramount, voicing opinions and thinking outside the box in a professional and appropriate scientific/medical manner is encouraged. Decisions are made as a team and the group’s culture is one that understands there is no “only” way to do things. Hard work and critical thinking are highly valued and expected. The NDD/MDS franchise is critically important to the success of Teva as a whole.

Key responsibilities include:

  • Lead and develop the Huntington’s disease clinical development program for compounds in late phase global clinical development. This includes direct oversight and management of the clinical development trials and compounds.
  • Responsible for developing the overall clinical strategy for the Huntington’s disease franchise and provide medical and scientific support to current and future commercialized products.
  • Responsible for Global Clinical Development Phase II/III trial activities and in protocol development, study execution and interpretation of results.
  • Close collaboration with Teva Global Medical Affairs and strong relationships with Key Opinion Leaders in the Huntington’s disease space.
  • Help develop the commercial strategy for compounds in late phase clinical development and attend sales meetings and other commercial meetings/activities as needed.
  • Interface effectively with other Clinical Development functions and other departments, including Clinical Operations, Biometrics in design and conduct of the clinical programs.
  • Work closely with Marketing, Medical Affairs, Regulatory Affairs and Pharmacovigilance in development of clinical plans that meet both regulatory and commercial needs.
  • Highly important member of the Vice President’s management team; makes go/no go decisions on the pipeline and key decision maker in what the company does in Huntington’s Disease in the present and future.
  • Create and maintain a positive and productive work environment and exhibit exceptional leadership capabilities by creating trust and respect within Huntington’s Disease clinical development as with other colleagues in Teva.
  • Need to support critical evaluations and recommendations of business development opportunities in the respiratory area working with colleagues from the Search and Evaluation Team and business development.

Candidate Profile

The ideal candidate will demonstrate the following qualifications and competencies:

  • M.D., Board Certified (Neurology, Psychiatry, etc.) or Clinical Geneticist with Strong Clinical Knowledge of Huntington’s disease. (Neuroscientist or Neurology or Psychiatry.) Minimum of 10 years’ experience in a clinical development function within a biotech or pharmaceutical company.
  • Outstanding proven track record in Huntington’s disease drug development; intimate understanding of Huntington’s disease a must.
  • Experience filing multiple New Drug Applications (NDA’s) preferred.
  • Strong relationships with Huntington’s disease Key Opinion Leaders (KOL’s) across the country and globe.
  • Well-developed leadership skills with the ability to influence, able to make decisions and stand by them. This individual will be highly visible at all levels of the organization and must be able to build trust and credibility walking in the door.
  • Exceptionally sharp thinker; ability to push innovation and creative thinking. Strategic thinking, accountable and forward-looking; able to see larger business picture.
  • Flexible, work in a fast-paced environment and be open to change or the unknown.
  • Collaborative and proactive, with a hands-on, roll-up-the-sleeves style and attitude.
  • Excellent interpersonal, presentation and communication skills.
  • If interested, please call/send CV to:

Al DiPalo
Sr. Strategic Sourcing Partner
Teva Pharmaceuticals

Career Opportunity: Director/Sr. Director Global Specialty Development, Neurodegenerative Diseases, Teva

teva_cns_logoDirector/Sr. Director Global Specialty Development, Neurodegenerative Diseases

The Role

The Director/Sr. Director is responsible for the development, execution and management of multiple clinical programs worldwide across all phases of clinical research in the areas of Neurodegenerative Diseases (NDD). Reporting to the VP, Global Head of NDD Clinical Development, the Director/Sr. Director will oversee clinical study teams, represent the clinical development department in functional area teams, and will be responsible for leading cross-functional teams in a matrix environment.

The individual is expected to be able to function independently in the daily management of clinical research projects including the preparation/review of related key documents (i.e. protocols, Investigator’s Brochures, clinical study reports, summaries for regulatory submissions). He/she will be the point person for all clinical questions (e.g. methods, safety) that arise on specific protocols and programs under his/her responsibility.

Key responsibilities include:

  • The Director/Sr. Director will responsible for the clinical development plan and will provide leadership for assigned asset strategy, working closely with other functional areas such as commercial, regulatory, pharmacovigilance, CMC, and pre-clinical development in this regard.
  • The Director/ Sr. Director will be a key contributor to and responsible for the clinical leadership of INDs, NDAs, BLAs, and other global regulatory filings. The Director/Sr. Director will engage in scientific interactions foster relationships with opinion leaders in the field of migraine and headaches.
  • Will be a core member of the Global Project Team
  • Will have and maintain the expertise necessary for the clinical development of the product
  • Prepares and manages multiple Clinical Development Plans
  • Leads or oversees the cross-functional clinical development team
  • Supports Global Clinical Operations in clinical trial initiation, resource planning, study implementation and successful completion
  • Makes presentations at the Investigator Meetings and other relevant internal or external
  • Responsible for identifying human resources requirements to implement the Clinical Development Plan
  • Works with Clinical Supplies Group to ensure clinical drug supply plans and timely procurement with the clinical supplies group
  • Ensures clinical trials comply with clinical guidance, ICH, GCP, in agreement with the laws of the relevant countries and Teva Standard Operating Procedures
  • Resolves safety or relevant clinical issues in consultation with Global Drug Safety and Pharmacovigliance, VP Clinical Research and the Head of the Global Respiratory Therapeutic Area as needed.
  • Oversees the preparation of documents for IND/NDA/MAA and other regulatory documents
  • May lead an NDA/MAA submission team independently, as needed
  • Partners cross-functionally with departments such as Regulatory Affairs, Toxicology, CMC/Formulations, Biostatistics, Legal, Marketing, Accounting/Finance, GCO, and GCPR in the execution of Clinical Development Plans
  • Capable of analyzing and interpreting clinical results and provide a guidance to prepare high quality reports working with Medical Writing
  • Responsible for authoring protocol synopses and working with Medical Writing. Provides input and direction to the review and finalization of Protocols, Clinical Study Reports and other relevant clinical documents
  • Author and/or review abstracts, posters and manuscripts, present data at scientific meetings, as needed
  • Represent Teva at Scientific meetings, advisory boards, KOL boards and meetings with regulatory agencies, as needed

Candidate Profile

  • MD, DO or equivalent combination of education and related work experience. PhD, PharmD with strong proven track record will be considered
  • At least 3 years’ experience in a pharmaceutical industry environment or related area planning/managing clinical trials, with proven ability to manage projects and/or lead project teams effectively. MD/DO without prior industry experience but with relevant knowledge and expertise in clinical trials will be considered
  • Experience in neurodegenerative disease, movement disorders, rare diseases (CNS) therapeutic areas is strongly preferred (Huntington’s Disease, Parkinson’s disease, Alzheimer’s disease, Motor Neuron Disease/ALS)
  • Excellent interpersonal, verbal and written communication skills. Ability to manage multiple conflicting priorities and varied concurrent tasks, 2-4 years of managerial experience preferred
  • Strong sense of urgency and understanding of time pressures, ability to thrive and enjoy working independently in a fast-paced, multi-tasking environment

If interested, please call/send CV to:

Al DiPalo
Sr. Strategic Sourcing Partner
Teva Pharmaceuticals

Meet the Next Generation

The global HD research community continues to grow and welcome a new, diverse generation of investigators. As we did in 2015, HD Insights interviewed next-generation HD researchers who have been invited by the HSG to attend the 2016 HSG Annual Meeting. We bring you their backgrounds, their current work, and their vision for the future of HD research.

Shoulson Scholar


Dr. Nora Fritz

Name: Nora Fritz, PhD, PT, DPT, NCS
• BS, Zoology, Miami University, Oxford, OH
• DPT, Physical Therapy, The Ohio State University, Columbus, OH
• PhD, Rehabilitation Science, The Ohio State University, Columbus, OH
• Postdoctoral Fellowship, Johns Hopkins University, Baltimore, MD
Current position: Assistant Professor of Physical Therapy and Neurology, Wayne State University, Detroit, MI
Hobbies and interests: Traveling and gardening
Current research interests: Dr. Fritz began working with individuals with HD during her doctoral work, as both a consulting physical therapist in the HD clinic, and during research studies, including a clinical trial that examined the influence of a video game on balance, and a multi-center trial that examined the reliability of physical performance measures. Since completing her PhD, Dr. Fritz has maintained a strong working relationship with the European Huntington’s Disease Network. Dr. Fritz joined the Physical Therapy & Neurology faculty at Wayne State University in 2015.
She serves as the principal physical therapist for the Wayne State University HD Clinic, and directs the Neuroimaging and Neurorehabilitation Laboratory. The overarching research goal of the laboratory is to develop novel rehabilitation strategies that target motor and cognitive decline in individuals with neurodegenerative diseases such as HD. Dr. Fritz’s lab is currently examining motor and cognitive performance over time to establish patterns of change, and biomarkers that might indicate future impairment.
Hopes for the future of HD research: Dr. Fritz hopes that clinical trials that examine non-pharmacologic interventions will improve the function and quality of life of individuals with HD, their care-givers, and families.
Publication highlight: Fritz NE, Hamana K, Kelson M, et al. Motor-cognitive dual-task deficits in individuals with early-mid stage Huntington disease. Gait Posture. 2016 Jul 17;49:283-289. doi: 10.1016/j.gaitpost.2016.07.014. [Epub ahead of print]

Shoulson Scholar


Dr. Martin Kronenbuerger

Dr. Martin Kronenbuerger

Name: Martin Kronenbuerger, MD
• MD, University of Heidelberg Medical School, Heidelberg, Germany
• Residency in Neurology, RWTH Aachen University Medical School, Aachen, Germany; Privatdozent (German academic title comparable to PhD)
• Medical Faculty RWTH Aachen University, Aachen, Germany
Current position: Movement Disorders Fellow, Parkinson and Movement Disorders Center, Johns Hopkins University School of Medicine
Hobbies and interests: Outdoor activities with family, including hiking and mountain camping
Current research interests: Dr. Kronenbuerger worked as an attending neurologist at academic centers in Germany and the Netherlands, until his interest in movement disorders led him to join the Movement Disorders team at Johns Hopkins Hospital as a fellow. During a rotation with Dr. Christopher Ross at the Johns Hopkins HD center, Dr. Kronenbuerger began working with HD patients and became involved in HD research. He and his colleagues are currently investigating MRI changes in premanifest and manifest HD, hoping to develop a sensitive marker of disease progression that can be used in future clinical trials of disease-modifying therapies. They are beginning a one-year follow-up study with their original cohort to assess MRI changes and evaluate their model.
Hopes for the future of HD research: “We are on a good path,” Dr. Kronenbuerger said, “because medications such as laquinimod that have been shown to be effective for other neurological diseases are now being evaluated in HD.” He is hopeful that MRI markers for disease progression will finally enable the trials necessary to develop disease-modifying treatments.
Publication highlight: Kronenbuerger M, Hua J, Unschuld P et al. Cortico-striatal functional connectivity in premanifest and manifest Huntingon’s disease measured with high-field functional MRI. [abstract]. To be presented during the Tenth Annual Huntington Disease Research Symposium, November 3rd, 2016, Nashville, TN.

HDSA Human Biology Fellow

Dr. Regina Kim

Dr. Regina Kim

Name: Regina Kim, PhD
• PhD, Large-scale MRI processing/Biomedical Engineering, University of Iowa, Iowa City, IA
Current position: Research Scientist, University of Iowa, Iowa City, IA; Research Professor, Korea University, Ansan, Korea
Hobbies and interests: Rock-climbing and other exercise
Current research interests: Dr. Regina Kim became involved in HD research when she came to the University of Iowa to earn her PhD in Biomedical Engineering, with a focus on large-scale MRI processing. With the help of Dr. Hans Johnson, Dr. Kim began her research on the large dataset generated by the PREDICT-HD study. Her work focuses on analysis of large-scale biological datasets, with a particular focus on imaging analysis. She is just finishing her HDSA-funded project analyzing volumetric MRI data from the PREDICT-HD study, hoping to use the super-computing power of the University of Iowa’s high-performance computing resources (see HD Insights, Vol. 7) to identify changes in the brains of HD patients. Her work aims to not only confirm and further characterize the changes in volume already observed in the caudate and putamen, but also to identify volumetric changes in approximately 125 additional regions of the brain, to better characterize the progression of HD in the premanifest and prodromal periods. Her team seeks to identify a spectrum of changes within the brain which can not only provide a biological signature of HD progression, but which may also give insights into the symptomatology of the disease.
She hopes that these imaging markers may be combined with biological markers and other imaging modalities to provide a sensitive, objective assessment system for future HD trials.
Hopes for the future of HD research: “It was 10 years ago that I started [doing research in HD], and people were saying that ‘there is no cure for HD, and we’re still just trying to understand the process.’” Now, we’re working on clinical trials, she says. She “won’t say for sure,” but hopes to see a disease modifying treatment on the market within the next ten years.
Publication highlight: Kim EY, Lourens S, Long JD, Paulsen JS, Johnson HJ. Preliminary Analysis Using Multi-atlas Labeling Algorithms for Tracing Longitudinal Change. Front. Neurosci. 2015, 9(242). doi: 10.3389/fnins.2015.00242. eCollection 2015.

HDSA Human Biology Fellow

Dr. Dawn Loh

Dr. Dawn Loh

Name: Dawn Loh, PhD
• BSc, Genetics, University of Edinburgh, Edinburgh, UK
• PhD in molecular genetics, MRC Human Genetics Unit, University of Edinburgh, Edinburgh, UK
Current position: Project Scientist with the Department of Psychiatry and Biobehavioral Sciences at the University of California Los Angeles, CA
Hobbies and interests: Camping and hiking with her family in the outdoors of California
Current research interests: Dr. Loh began her studies by completing an undergraduate degree in genetics. The HD gene was discovered during her studies, which catalyzed her interest in the disease. She completed her PhD in Edinburgh, then took a post-doctoral position at UCLA with a mentor who focused on sleep-wake timing and the biology of circadian “clocks.” Their work in mouse models of neurodegenerative disease included explorations of sleep-wake dysregulation in HD mouse models that express varying CAG repeat lengths.
After six years exploring the striking neurological basis of these disruptions in mice, Dr. Loh is currently investigating sleep disruption in human HD patients through her HDSA Human Biology fellowship. Her project utilizes an at-home activity monitor used throughout sleep research that enables comparison of the sleep-wake patterns of HD patients and age-matched controls. She is primarily interested in identifying sleep-wake cycle disruption in HD patients, and understanding the biology of this disruption. She hopes that future research might determine whether sleep hygiene education or other methods of improving sleep quality might improve sleep in HD patients, and perhaps even slow the progression of the pathology.
Hopes for the future of HD research: Dr. Loh is excited about the move toward nucleotide-based therapies, and hopes that they will be a game changer. In the absence of an effective disease-modifying treatment, she hopes to see more research into the peripheral effects of HD, and more integration of whole-body outcome research.
Publication highlight: Loh DH, Jami SA, Flores RE, et al. Misaligned feeding impairs memories. Elife. 2015 Dec 10;4. pii: e09460. doi: 10.7554/eLife.09460.

HDSA Human Biology Fellow

Dr. Sonia Podvin

Dr. Sonia Podvin

Name: Sonia Podvin, PhD
• BA, Biochemistry, Wellesley College, Wellesley, MA
• PhD, Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA
Current position: Assistant Project Scientist, Laboratory of Dr. Vivian Hook, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, CA
Hobbies and interests: Open-ocean swimming; karate
Current research interests: Dr. Podvin has dedicated her career to studying mechanisms of neurodegeneration. Her current work in HD focuses on identifying and characterizing proteins and peptides that interact with HTT in human brain tissues obtained from HD brain banks, and evaluating differences in these interactions between human tissue and available animal models using bioinformatics and systems biology. Understanding the protein molecular interactions that go awry in HD will point to potential therapeutic target testing for discoveries into novel therapies for HD patients.
While acquiring and analyzing proteomics mass spectrometry data from human HD brain tissues, Dr. Podvin is also working on a manuscript that evaluates a curated list of all available published HTT interactors in the field from animal and cellular HD models that she has collated, to utilize as a reference dataset. Analyzing the HTT interactors in animal and cellular models versus those in human tissues can facilitate understanding of similarities and differences between non-human HD model systems and humans, for use in future preclinical testing platforms. Her lab plans to manipulate the interactor proteins they have discovered in human patient-derived stem cell models to evaluate them as potential therapeutic targets.
Reflecting on her experiences at this year’s HDSA meeting, Dr. Podvin said that she was moved by how HD patients and families handled the development of this disease with so much courage, grace, and strength. Hearing from patients, their families, and their advocates gave her a new appreciation of the urgency with which treatments are needed. She is excited to be attending the HSG meeting to discuss the ways in which veteran HD researchers and clinicians use neuroscience in their clinics to improve care for their HD patients, and how she can incorporate their invaluable knowledge-base to plan future research strategies.
Hopes for the future of HD research: Through her work, Dr. Podvin hopes to contribute to the growing body of publicly available data on the biology of HD to speed the search for new treatments. She also hopes to better characterize differences between HD biology in humans and HD animal models to improve translation of novel therapies.

Scholars invited to HSG 2016:
2016 Shoulson Scholars
Nora Fritz, PhD, PT, DPT, NCS
Martin Kronenbuerger, MD

HDSA Human Biology Fellows
Regina Kim, PhD
Dawn Loh, PhD
Sonia Podvin, PhD

Editor’s Letter

Editor's letter featured imageWelcome to the 15th edition of HD Insights, released at the 2016 Huntington Study Group (HSG) Annual Meeting in Nashville, TN. We are proud to be celebrating five years of pursuing our mission to promote, disseminate, and facilitate HD research with content that is valuable and informative to the global community of HD researchers. This 15th edition marks the third year of our Insights of the Year competition, the second of our Meet the Next Generation of HD researchers feature, and the continuation of our updates on HD clinical trials, compounds in development, and research from around the world. We are grateful to our sponsors, our readers, and our authors for their contributions towards our ongoing mission.
This year, our Editorial Board and last year’s Insights of the Year winners nominated 17 articles as the most influential developments in HD research from July 2015-July 2016. All 17 explore fascinating and promising discoveries and advancements in our understanding of HD and in our attempts to develop treatments. The three winners, selected by the Editorial Board and previous awardees, will be presenting their work at a panel session at the HSG meeting on November 2. Also at this year’s meeting, the 2016 HDSA Human Biology Fellows awarded scholarships to attend HSG and the two 2016 Shoulson Scholars, featured in our “Meet the Next Generation” series, will be presenting their research and connecting with new and veteran investigators and researchers from around the world. This edition also brings you an update from Dr. Kimberly Kegel-Gleason on the promise and opportunities in the use of induced pluripotent stem cells in HD research, a highlight from the Journal of Huntington’s Disease. Dr. Joseph Ochaba shares his work exploring potential therapeutic targeting of PIAS1 to diminish neurodegeneration. We sit down with WAVE Life Sciences, a new biotechnology company using proprietary techniques to produce stereopure nucleic acid therapies for HD and other rare diseases, and introduce you to their new compounds. Finally, we continue to update the HD community on upcoming, ongoing, and recently completed clinical trials.
HD Insights is dedicated to creating connections and bringing together ideas and people in the HD community to advance HD research. This edition features job opportunities both for those in training and at a later stage in their careers, in academia and in industry. If you have an opportunity you would like to share with nearly 3000 HD researchers and clinicians, please let us know at editor@hdinsights.org.
Your comments, suggestions, and contributions are invaluable to us. If you would like to get in touch, please email editor@hdinsights.org. If you or your colleagues would like a free electronic subscription to HD Insights, please visit www.HDInsights.org and complete the subscription form. Thank you for all that you do.
-Ray Dorsey, Editor, HD Insights
disclosures: dr. dorsey receives grant support from prana biotechnology, teva, roche, biomarin, raptor pharmaceuticals and the huntington study group.