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Huntington’s Disease: Revolutionizing Drug Discovery with Fast In Vivo Models

Small animal models like C. elegans and Zebrafish will be essential tools if we are to find a cure for Huntington’s Disease.

Huntington’s Disease Awareness Month is an opportunity to recognize those affected by the disorder and the challenges that remain in finding treatments. Despite its discovery over a century ago, Huntington’s Disease remains a formidable affliction, with limited treatment options available to slow its progression.  In this post, we discuss how zebrafish and nematodes have contributed major milestones to our understanding of the disease and how these small animal models will ultimately play a critical role in finding effective treatments.

Key Points

Infographic indicating the genetic modeling approaches and assay readouts for Zebrafish and C. elegans models of Huntingtons's disease.

Introduction

Huntington’s Disease Awareness Month is an opportunity to recognize those affected by the disorder and the challenges that remain in finding treatments.  Huntington’s Disease (HD) is an autosomal dominant genetic neurodegenerative disorder, stemming from an aberrant CAG repeat expansion in the huntingtin gene (HTT). This mutation results in a long polyglutamine (polyQ) repeat in the huntingtin protein, rendering it prone to aggregation. Unsurprisingly, the length of these repeats directly correlates with the severity of the disease.

Despite its discovery over a century ago, Huntington’s Disease remains a formidable affliction, with limited treatment options available to slow its progression. Patients, on average, succumb within a mere two decades of diagnosis. However, amidst this challenge, small animal models have propelled significant strides in understanding the functions of the huntingtin protein and the pathological mechanisms underlying the disease.

As Huntington’s takes 30-50 years to quietly unfold, no animal model can faithfully capture the full trajectory of the disease.  For these prolonged disorders, the key strategy to understand and treat the disease is to leverage the animal models that provide the best window on the cellular pathology of the disease.  Among these models, zebrafish and C. elegans stand out as clear leaders, offering unparalleled advantages in terms of speed, throughput, and anatomical visibility.

Zebrafish provide a clear window on Huntington’s pathology.

For modeling Huntington’s and other neurodegenerative disorders, zebrafish provide not only anatomical visibility but also behavioral phenotyping capabilities that outshine traditional rodent models. Remarkably, the zebrafish homolog of the human HTT gene shares an impressive 70% identity, with expression patterns in brain regions analogous to those affected in humans with Huntington’s.

One pivotal advantage of the zebrafish model lies in its viability even in the absence of functional HTT, a stark contrast to rodents. This unique trait has paved the way for crucial developmental studies elucidating HTT function. Moreover, zebrafish engineered to harbor Huntington’s mutations exhibit cellular and behavioral hallmarks mirroring the disease, bolstering the clinical relevance of this model.

The optical clarity of zebrafish embryos offers a direct window on protein aggregation and neurological defects within the brain. This transparency facilitates the monitoring of protein aggregation dynamics, alongside cellular and anatomical aberrations. Furthermore, the adaptability of zebrafish for high-throughput chemical screening empowers researchers to screen for compounds capable of inhibiting protein aggregation rapidly. Additionally, high-throughput behavioral screening has become widely adopted in zebrafish and offers a speed and throughput not remotely accessible in rodent models.

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C. elegans is the fastest in vivo model for understanding and ameliorating protein aggregation.

For modeling protein aggregation diseases, C. elegans emerges as the undisputed champion in terms of speed and economy. These humble nematodes, offer two types of genetic models for Huntington’s Disease.  One is a basic model that expresses naked polyQ repeats fused to a fluorescent protein reporter.  This model captures fundamental aspects of polyQ aggregation and faithfully recapitulates the length-dependent toxicity of polyQ repeats. More specific models involve polyQ repeats of varying lengths inserted into a fluorescently tagged huntingtin protein or patient-derived mutations introduced into these reporters.  

These fluorescent models enable researchers to observe aggregate accumulation within 4-5 days rapid screening for compounds that mitigate aggregation. While C. elegans may not fully replicate all anatomical and behavioral aspects of Huntington’s Disease as zebrafish do, it offers a reductionist in vivo-in vitro platform for swiftly testing functional hypotheses and screening potential therapeutic compounds.

Conclusions

Finding treatments for Huntington’s disease will at least require an expanded inquiry of potential treatments that can be best achieved with small animal models at the front line.  At InVivo Biosystems, we recognize the urgency and complexity of Huntington’s Disease and other neurodegenerative disorders. Leveraging our expertise in genome editing, we’ve empowered numerous clients to create relevant disease models across this spectrum of diseases. From zebrafish to nematode worms, we stand ready with extensive experience in cellular, anatomical, and behavioral approaches to studying protein aggregation diseases.

We’ve witnessed firsthand the transformative impact that small animal models can have on addressing challenging diseases, sometimes yielding breakthroughs for the seemingly incurable. With optimism and determination, we embrace the challenges ahead, fueled by the shared mission to accelerate discoveries and ultimately pave the way toward effective treatments for Huntington’s Disease and beyond.

About The Author

Adam Saunders

After studying music at Indiana University, Adam pivoted into biology where he was introduced to C. elegans while working with Dr. Susan Strome and Dr. Bill Saxton. From there, Adam earned a Ph.D. from the Stanford University School of Medicine with Dr. Phil Beachy. In his thesis work, Adam investigated how signaling proteins essential for animal development are packaged and transported through the body. As a postdoctoral researcher with Dr. Victoria DeRose at the University of Oregon, Adam studied how beneficial and disease-causing bacteria use structured RNAs to detect nutrients with a human host. While at Oregon, Adam also taught advanced biology courses and served as a STEM outreach coordinator. Adam joined NemaMetrix (now InVivo Biosystems) as a Research and Development Scientist in April 2019. One of his roles is to oversee experimental design and execution of custom research projects. Adam still plays music–joining groups or jam sessions in the Eugene area–and also enjoys exploring the Oregon mountains by ski or by foot.

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