Ariella Pharmaceuticals
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Huntington's Disease
The most abundant autosomal neurodegenerative disorder
Huntington’s disease (HD) is an age-onset, genetically inherited neurological disorder with a global prevalence of 4.88 individuals per 100,000 worldwide, affecting approximately 1 in 7,300 people in Western populations (1, 2). HD manifests with a combination of progressive symptoms in motor control, cognitive and behavioural impairments, ultimately leading to death around 20 years after the onset of symptoms (2).
The causes, genetics, and epidemiology
The HD is caused by the expansion of the CAG repeat in exon one of the HTT gene, responsible for encoding the huntingtin protein (3). This expansion leads to the synthesis of a mutant huntingtin (mHTT) protein, characterized by an abnormal polyglutamine (polyQ) sequence (3). The misfolded mHTT accumulates in neurons, particularly in the striatum, causing toxicity that results in dysfunction and neuronal death throughout the brain (2).
Owing to the HD's dominant inheritance pattern, most individuals carrying one mutant HTT (mtHTT) gene with a longer CAG repeat than the wild-type HTT (wtHTT) gene are predisposed to toxic gain of function in mHTT, with some rare exception of being homozygous to mtHTT and consequent more severe symptoms (2, 4). The CAG repeat expansion not only influences the age of onset but also shapes the pace of pathophysiology that gives rise to diagnostic motor signs (2). However, CAG repeat exhibits somatic instability, which will expand continuously throughout life, and passing the lengthened repeat to offspring (5).
HD exhibits varying prevalence rates across populations, with individuals of European ancestry being more affected (2). Nowadays, with an aging population, increased life expectancy, and advanced molecular testing, the prevalence of HD is on the rise (2). Ariella Pharmaceuticals is at the forefront of addressing these emerging trends, anticipating the growing demand for ongoing HD treatment.
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The mechanism and pathophysiology: complex and universal
The journey through HD's pathophysiology is influenced by multiple factors. The level of expression of mutant huntingtin, the length of the CAG repeat, and the extent of proteolysis all plays pivotal roles (2). Abnormal expression of mtHTT disrupts proteostasis networks, which is responsible for maintaining the delicate balance of proteins and cellular homeostasis. This interference results in a decline in molecular chaperones, placing stress on and compromising protein degradation pathways, including ubiquitin-proteasome degradation and lysosome-autophagy degradation pathways (2).
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One of the cascades of pathological events in HD is when concentration of the toxic exon 1 HTT fragment reaches a critical threshold (2). This highly toxic primary pathogenic species is exclusively found in affected individuals (6). Two pathways generate these fragments: (a) proteolysis (cutting) of the full-length huntingtin protein and (b) direct translation of fragments due to aberrant splicing of HTT mRNA (2). Synthesized fragments translocate into the nucleus, undergoing oligomerization and aggregation to form amyloid fibrils and intranuclear inclusion bodies (5). The effects of inclusion bodies are as diverse as the locations they inhabit.
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Affected indiviuals have observable atrophy in several brain regions, including the caudate, even before the onset of motor impairment. As HD progresses, individuals experience substantial loss of neurons in cortical, thalamic, and hypothalamic regions, ultimately spanning the entire brain (4).
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Figure 1. The cellular mechanism of the development of Huntington disease (2). Steps 1–7 indicated the pathogenic progression, starting from the aberrant translation of mutant Huntingtin to the dysregulated transcription and global cellular deficits.
​Look into the simple video below about what is Huntington's disease (7):
​Pioneering Therapies: fuelling medical needs
There is no available direct cure for Huntington’s disease (HD). Most of the approved HD drugs work by addressing the symptoms of the diseases, but not the origin (8). Moreover, each affected individual has a unique set of symptoms, necessitates a diverse array of prescription and non-pharmacological therapies to address the corresponding symptoms (8).
The horizon of potential HD therapies is shifting towards a revolutionary approach — lowering the mHTT protein. The nucleic acid therapies are currently at the forefront of the therapeutic research, with the largest ongoing phase 3 clinical trials with the drug Tominersen (4). However, the trial was halted due to safety and tolerability concerns (4).
At Ariella, we stand at the forefront of progress in nucleic acid therapies for Huntingtin lowering. Our cutting-edge advancements on developing Nominsen® enable the direct targeting of mHTT, leaving the wild-type Huntingtin (wtHTT) protein unaffected. Our commitment to pioneering these innovative approaches reflects our dedication to ushering in a new era of therapeutic possibilities for those affected by HD.