Huntington’s Disease (HD) is inherited as an autosomal dominant trait caused by a single mutated copy of the HTT gene (mHTT) [1]. This mutation results in the production of an expanded form of the protein huntingtin, causing a toxic gain of function that eventually leads to neuronal degradation [5].
Introduction
A rare disease as defined by the Orphan Drug Act is a disease that affects fewer than 200,000 people in the United States. Within these parameters, there are over 10,000 known rare diseases, one of which is Huntington’s Disease [3]. Huntington’s Disease is thought to affect about 1 in every 10,000 people and is a hereditary neurodegenerative disorder caused by a single mutated allele located on the HTT gene on chromosome 4. The mutation (mHTT) is an expansion of the CAG repeat at the 5’ end of the HTT gene that results in an elongated and abnormal polyglutamine chain in the huntingtin protein. Over-production of this mutant form of the huntingtin protein subsequently leads to neuron death [5].
Individuals with the HTT gene mutation will develop the disease in their lifetime; most develop symptoms beginning in middle age, but symptoms can develop at any point. There is currently no cure for Huntington’s Disease or treatment options that halt the progression of HD, but we are hopeful as there are currently therapeutics in clinical trials (as of April 2023) to address the root cause of the disease. Below, we will document the genetics, research, and clinical details of this disease, as well as explore the possibility of a future RNA therapeutic.
Tell Me About This Rare Disease
Genetic basis: Huntington’s Disease is caused by a mutation in the HTT gene, locus on human chromosome 4p16.3 [6], inherited in an autosomal dominant fashion; however, HD can also occur without a family history (sporadic HD) [2]. The HTT gene encodes a protein called huntingtin. When the mutation is inherited or sporadically occurs it causes abnormal expansion of the polyglutamine tract in the N-terminus of huntingtin [6], leading to a trinucleotide repeat ranging from 36-120 CAG copies in one allele on the 5’ end of the gene [2] [5] [6] [7]. For reference, most healthy individuals have an average of 10-35 CAG copies [7]. This expansion causes an abnormally elongated version of the huntingtin protein, which is then cut into smaller, toxic pieces that bind together and accumulate in neurons located in the brain [7]. This accumulation causes neuronal degeneration and eventually leads to neuron death [7] [10].
Clinical Presentation: Early signs of HD may appear in many different forms including mild clumsiness or balance problems, cognitive or psychiatric troubles, and/or noticeable changes in behavior. These mild symptoms eventually progress to uncontrollable movements (chorea), difficulty walking, body rigidness (akinesia), unusual and fixed postures (dystonia), tremors, unusual eye movements, slurred speech, problems swallowing, fatigue, seizures, and more [2].
Incidence: There is little known about the incidence of Huntington’s Disease and the prevalence appears to vary across different ancestries and geographic locations [8]. However, it is thought that approximately 3-7 per 100,000 people of European ancestry are affected by HD [7][8]. HD appears to be less common among other regions and populations including but not limited to those of Japanese, Chinese, and African descent [7]. These estimates likely need revising as current research on HD incidence is limited.
Geographical locale of patients: As mentioned above, geographic locale appears to play a role in the incidence of this disease. HD seems to be most prevalent across Northern Europe and in those of Northern European descent [8].
Brief History:
1842: The disease was first mentioned in a letter written by Charles Oscar Waters, published in the Practice of Medicine [9].
1872: George Huntington gave the first complete description of the disease [9].
1993: US-Venezuela Huntington’s Disease Collaborative Research Project reported the locus of the mutated gene at 4p16.3 [9].
2008: Tetrabenazine, a drug that treats HD-associated chorea is approved by FDA
2017: Deutetrabenazine, a drug that treats HD-associated chorea is approved by FDA
2017: IONIS Pharmaceuticals developed the first potential antisense oligonucleotide (ASO) treatment, tominersen, for HD and completed a Phase 1/2a clinical trial [12].
2021: Wave Life Sciences started dosing a potential ASO therapeutic in Phase 1b/2a PRECISION-HD1 and PRECISION-HD2 trials [14]
2021: Dosing of tominersen was announced to stop in GENERATION-HD1 after little to no improvements were found in treated patients and frequent dosing showed greater adverse reactions [12].
2022-2023: Wave Life Sciences’ ASO Therapeutic WVE-003 (SELECT-HD TRIAL) [13]
The state of the disease today: The majority of treatments available to HD patients today aim to treat the symptoms of the disease, while there are no targeted therapeutic options readily available. Today there are several ASO therapeutics in human trials including IONIS’ tominersen and Wave Life Sciences’ WVE-003 (SELECT-HD TRIAL), however neither of these have FDA-Approval [13].
What is it like to be a patient with this disease?
Who are the patients? Patients with HD typically start experiencing symptoms when they are middle-aged (adult HD). However, symptoms may appear as early as childhood (juvenile HD), but this is rare [2]. People living with HD will experience an increase in symptoms as they age that will progressively worsen until they can no longer work, drive, or care for themselves. The disease often leads to dementia and death 10-30 years after the onset of symptoms [10].
What do current treatment options look like? As previously mentioned, there is currently no cure for HD or treatment options that halt the progression of the disease. Currently, patients only have options to treat symptoms stemming from the disease. Classes of treatments include chorea medication, antipsychotic medication, antidepressants (SSRIs), and mood stabilizers [16]. Involuntary movements and other motor issues are currently treated by tetrabenazine, deutetrabenazine, amantadine or antipsychotic drugs such as haloperidol. Antidepressants and antianxiety medications are also prescribed to help with depression and anxiety, which is commonly experienced by HD patients [17].
Are there advocacy groups? There are several large HD advocacy groups and resources for patients in the United States. The Huntington’s Disease Society of America is a non-profit organization that carries out community services, education, advocacy, and research to improve the lives of people affected by HD. They also host support groups for individuals across the spectrum in age and stage of disease [18]. The Huntington’s Disease Youth Organization is a non-profit organization that supports, educates, and empowers young people who are affected by HD. HD Buzz is a website dedicated to news about HD research.
Are there genetic tests? Yes, genetic tests in the form of a blood sample are available to individuals to diagnose HD. A complete medical history is performed along with lab tests for individuals at risk of carrying the mutated HTT gene [19].
How do Scientists and Clinicians Study this Disease?
Are there any (good) model systems for drug development? No singular model has been able to replicate the complexities of human HD. Various models of HD exist to study the disease which include cellular models containing the mHTT gene and transgenic in-vivo mouse models. The existing models, all together, have helped scientists gain a better understanding of HD, but each has its own limitations. In addition, it is difficult to create an all-encompassing model as the size of the mutated gene varies from patient to patient [20] [21].
Certain physicians or centers that are experts? There are many academic scientists and large groups focused on HD research. For example, Dr. Jeff Carroll at Western Washington University is working to create models of HD and is interested in using ASO technology to silence mutant genes. The Huntington Study Group is a research organization that focuses on facilitating clinical trials and conducting research specifically for HD.
What are the major challenges for studying and curing this disease? A major challenge for curing HD is the involvement of the HTT gene in diverse processes of the cell- the gene itself cannot be lowered unless its essential processes are maintained. Another challenge is the lack of a comprehensive animal model of HD, as previously mentioned. A third challenge is found when developing clinical trials because of the limited number of patients and the lack of quantitative clinical measures of HD [21].
The Cure Corner: What is needed for a cure?
What are current therapies and treatments lacking? Current therapies do not address the root cause of HD, only downstream symptoms associated with it. Due to this, there is an increased interest in developing a therapy that selectively lowers the production of mutant huntingtin protein.
What does an ideal therapeutic look like? An ideal therapeutic would target the mutated gene directly without influencing the gene’s role in the body. Preclinical in-vivo studies suggest that lowering the mutated transcript of the HTT gene can be an effective therapy for HD. In one study, when the mutant form of the Huntington gene was inactivated in mouse models of HD, the mice experienced a recovery of motor function and reversal of protein aggregates associated with HD [22].
Could an RNA therapeutic fit the need? Yes, an effective strategy of selectively lowering mutant HTT could be through RNA and DNA targeting which can be accomplished by an RNA therapeutic. RNA interference has been shown to ameliorate HD phenotypes by reducing mutant HTT gene expression [23]. ASO therapeutics are advantageous because they have a long half-life and broad distribution in the CNS as demonstrated by the drug Spinraza for treating SMA.
Are there companies already developing drugs? ASO therapies for modifying HD are among the first to enter clinical trials. For example, three ASO therapeutics designed to lower disease-causing protein were recently evaluated in clinical trials. Wave Life Sciences developed two allele-specific ASO therapeutics to selectively target the mutant HTT gene that ended in phase I/IIa trials. Roche and IONIS developed an ASO called tominersen to lower the HTT gene that reached phase III trials [24]. The committee ruled that groups treated with tominersen did not see an improvement over those in the placebo group and recommended to stop dosing patients in March 2021. From this study however, patients with early HD may have benefited from the drug so a new trial for patients with early HD is currently recruiting patients as of March 2023.
Conclusion
Much progress in research and clinical trials has been made to find a treatment to address the root causes of Huntington’s Disease. We hope that with an ASO therapeutic in clinical trials, HD may be treated head-on. However, even if not successful, further research will provide powerful data and get us closer to finding a cure for this devastating disease.
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[11] GENERATION HD2. A Study to Evaluate the Safety, Biomarkers, and Efficacy of Tominersen Compared With Placebo in Participants With Prodromal and Early Manifest Huntington's Disease. ClinicalTrials.gov identifier: NCT05686551. Updated April 18, 2023. Accessed April 27, 2023. https://clinicaltrials.gov/ct2/show/NCT05686551
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