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Much progress has been made in managing the symptoms of Huntington’s disease, but the real excitement lies in the development of disease-modifying drugs and genetic therapy.
In April 1872, The Medical and Surgical Reporter of Philadelphia published a roughly 3,000-word paper, titled “On Chorea,” by George Huntington, a 22-year-old family practice physician recently graduated from Columbia University, New York City.
“Chorea is essentially a disease of the nervous system. The name ‘chorea’ is given to the disease on account of the dancing propensities of those who are affected by it, and it is a very appropriate designation,” he wrote in the introduction.
Toward the end of the paper Dr. Huntington described a “hereditary chorea” that he had observed while on professional rounds with his father, also a physician, in towns on the eastern end of Long Island in New York.
“It is spoken of by those in whose veins the seeds of the disease are known to exist, with a kind of horror, and not at all alluded to except through dire necessity, when it is mentioned as ‘that disorder,’ ” he wrote, noting later that “I have never known a recovery or even an amelioration of symptoms in this form of chorea; when once it begins it clings to the bitter end.”1
It wasn’t until 1993 that a team of investigators identified the gene responsible for the neurodegenerative disorder we now know as Huntington’s disease.
That discovery sparked hope for better treatments and a cure, but progress over the last 31 years has been incremental. Nonetheless, recent intensive research into novel approaches for treating Huntington’s disease have considerably brightened prospects for patients and caregivers, experts say.
“This is a devastating neurodegenerative disease and in talking to families that I have had the privilege and honor of following, I hear from them that ‘in 1993 when the gene was identified and my family member — parent, grandparent, aunt, uncle — had Huntington’s, we thought that there would be a curative or disease-modifying therapy in no time,’ ” said Erin Furr Stimming, MD, FAAN, FANA professor of neurology and Memorial Hermann Endowed Chair at the McGovern Medical School at University of Texas Health Science Center in Houston.
“Here we are in 2024. I think our families are still so incredibly resilient and courageous, and they are willing and able to participate in clinical trials. Families in the Huntington’s disease community at large are really ready to have trials that do, in fact, demonstrate some evidence of slowing of disease progression. It’s an exciting time,” she said in an interview.
Repeating Nucleotides
Huntington’s disease is an autosomal dominant neurodegenerative disorder caused by an expansion of a CAG trinucleotide repeat in exon 1 of the huntingtin gene (HTT), which encodes for the huntingtin protein (HTT). The multiple repeats result in expanded expression of mutant HTT. The mutated protein disrupts normal cellular processes, alters intracellular calcium homeostasis, and interferes with gene transcription, leading to progressive degeneration of neurons, and to a hallmark Huntington’s disease triad consisting of movement disorders, cognitive decline, and mood/behavioral issues.
The number of repeats determines the severity of disease and the age of onset. In nonaffected persons the gene contains about 20 CAG repeats, but as genetics research dating from the 1990s has shown, a single HTT allele containing more than 40 CAG repeats will inevitably result in disease, whereas carriers with fewer than 36 repeats on both alleles will remain unaffected.2
The prevalence of the mutation in Western populations is estimated to be from 4 to 10 per 100,000.3
The disease usually manifests first in adults aged 30-50 years but may also occur in children or adolescents and young adults. Early symptoms often include a decline in executive function that may be noticeable to the patient’s family and friends, mood changes, and chorea.
“Because of the uncontrolled movements (chorea), a person with Huntington’s disease may lose a lot of weight without intending to, and may have trouble walking, balancing, and moving around safely. They will eventually lose the ability to work, drive, and manage tasks at home, and may qualify for disability benefits. Over time, the individual will develop difficulty with speaking and swallowing, and their movements will become slow and stiff. People with advanced Huntington’s disease need full-time care to help with their day-to-day activities, and they ultimately succumb to pneumonia, heart failure, or other complications,” according to the Huntington’s Disease Society of America.4
Managing Symptoms
say neurologists.
There are currently three medications approved for the treatment of chorea, all in the class of agents known as vesicular monoamine transporter 2 inhibitors. These agents are tetrabenazine (Xenazine, Lundbeck), deutetrabenazine (Austedo XR, Teva), and valbenazine (Ingrezza, Neurocrine Biosciences).
“These drugs can treat the chorea, but they also can help with some of the other motor features. For example, if a patient has chorea in the legs and you treat it, then maybe they’re walking will get better, or if they have chorea in the mouth and you treat the chorea, then maybe their speech and swallowing may improve,” Victor Sung, MD, professor of neurology and director of the Huntington’s Disease Clinic at the University of Alabama at Birmingham, said in an interview.
Mood and behavioral symptoms associated with Huntington’s disease – depression, anxiety, irritability, impulsivity, etc – can be managed with off-label use of antidepressants, mood stabilizers, and antipsychotic agents.
“When it comes to the cognitive symptoms, that’s a big gap where we don’t have anything that’s [Food and Drug Administration] approved for Huntington’s disease,” Dr. Sung said.
Agents used to treat Alzheimer’s disease, such as cholinesterase inhibitors and the glutamate receptor antagonist memantine, have been studied extensively for preservation of cognition in Huntington’s disease, but have not shown significant benefit.
Dr. Sung said that one promising approach to the problem of cognitive protection in Huntington’s disease is the investigational agent dalzanemdor (SAGE-718), an N-methyl-D-aspartic (NMDA) acid receptor positive allosteric modulator. The drug is in development for cognitive disorders associated with NMDA receptor dysfunction, including Huntington’s disease and Alzheimer’s disease.
In the phase 2 SURVEYOR trial, which was not powered to show efficacy of dalzanemdor over placebo, patients with Huntington’s disease reportedly tolerated the drug well, with treatment-related adverse events primarily mild or moderate in severity.
As of this writing dalzanemdor is being evaluated for efficacy, compared with placebo, in the phase 2 DIMENSION trial. The primary endpoint of this trial is a change from baseline in composite score of the Huntington’s Disease Cognitive Assessment Battery.
Disease-Modifying Therapies
As previously noted, although there is no cure for Huntington’s disease, neurology investigators are developing new strategies for delaying, stalling, or even preventing disease progression.
“There are so many different approaches, it’s hard to know where to start,” Christopher A. Ross, MD, director of the Huntington’s Disease Center at Johns Hopkins University in Baltimore, Maryland, said in an interview.
The most actively investigated approach may be huntingtin-lowering therapies, based on the supposition that mutant huntingtin protein (mHTT) is the primary toxin in Huntington’s disease.
“What you need to do is in some way lower it, and there are a number of different ways to do that: antinsense olignoclueotides, small interfering RNA, CRISPR Cas, or other gene-editing techniques, as well as gene therapy with an adenoviral vector” he said.
Gene Therapy
Dr. Ross cited as promising a phase 1/2 clinical trial of an investigational gene therapy, AMT-130 (uniQure), which consists of an adeno-associated virus vector and a gene encoding a microRNA that is designed to recognize, bind, and nonselectively lower both mHTT and wild-type HTT.
The compound is injected directly into the corpus striatum. It was demonstrated to decrease signs of Huntington’s disease in animal models, and interim data on 29 patients with Huntington’s disease followed for up to 24 months showed a statically significant, dose-dependent slowing of Huntington’s disease progression and lowering of neurofilament light protein, a marker for neuronal degeneration in Huntington’s disease, in cerebrospinal fluid (CSF).
AMT-130 targets exon 1 of the HTT gene, which appears to be an important target, Dr. Ross commented.
“The huntingtin protein is really big. The polyglutamine expansion, which is what causes the toxicity, is right at the N-terminus of exon 1, and there is increasingly good evidence that you can have an exon 1 misspliced protein product which causes the toxicity, so it may be especially important to lower Huntington by targeting exon 1,” he said.
Oral Splicing Modifier
PTC Therapeutics, based in New Jersey, is developing PTC518, an oral small molecule drug that can cross the blood-brain barrier and is reported to target mutant huntingtin protein.
The drug is a splicing modifier that promotes insertion of a premature stop codon to HTT mRNA, thereby degrading and lowering the HTT levels.5
In June 2024, the company reported that, in the phase 2a PIVOT-HD study of PTC518 in patients with Huntington’s disease, 12 months of treatment was associated with a dose-dependent lowering of mHTT in blood and CSF in an interim cohort.
“In addition, favorable trends were demonstrated on several relevant Huntington’s disease clinical assessments including Total Motor Score and Composite Unified Huntington’s Disease Rating Scale. Furthermore, following 12 months of treatment, PTC518 continues to be safe and well tolerated,” the company stated in a press release.
Antisense Oligonucleotides
Antisense oligonucleotides (ASOs) are short strands of DNA or RNA that bind to RNA sequences in faulty genes to modify production of target proteins.
One such drug, tominersen, developed jointly by Ionis and Roche, initially showed promise in a phase 1/2 trial for lowering mHTT in CSF without serious adverse events. But in a phase 3 trial, the intrathecally delivered agent was halted after an independent data monitoring committee recommended halting the trial, which Roche ended in 2021. The company reported in a letter to The New England Journal of Medicine that people in the high-dosage treatment group did measurably worse – although it remains unclear whether this was caused by excess protein lowering or an off-target effect.6 The tominersen program was the first to demonstrate that it was possible to lower HTT with an intervention, and the companies reported that they are continuing the agent’s development program.
Wave Life Sciences is developing an ASO, labeled WVE-003, designed to target a single-nucleotide polymorphism associated with the mHTT mRNA transcript within HTT. The company says that targeting the single-nucleotide polymorphism should allow lowering of expression of the mHTT will preserving wild-type HTT. This approach has the potential for therapies to prevent disease progression during the prodromal period, the company states.
Somatic Expansion
Dr. Furr Stimming and Dr. Ross both noted that there is considerable research interest into recently identified genetic modifiers that are believed to influence somatic instability, which in turn leads to somatic expansion.
“That seems to happen selectively in the neurons that are affected in Huntington’s disease. So a big puzzle for all of the neurodegenerative diseases is why are certain regions of the brain affected and other regions not? And it looks like, for the repeat expansion, this idea of somatic expansion seems to be increasingly central,” Dr. Ross said.
“The really exciting idea here is that, if somatic expansion is critical to the disease process and you could slow it down or stop it, you could go very early and potentially not just slow the progression of the disease once it starts, but conceivably even delay or possibly prevent the onset of Huntington’s disease,” he said.
Does HTT Lowering Mediate Progression?
“The next question is what does this mean clinically? Does lowering mutant huntingtin protein levels, and wild type for that matter, actually slow disease progression, which can be challenging to measure in a disease that is relatively slowly progressive?,” Dr. Furr Stimming said.
One important tool to help answer this question, she noted, is the Huntington’s Disease Integrated Staging System (HDISS), first described in 2022.7 The consensus-based system incorporates biological, clinical, and functional assessments, and characterizes patients from birth by stages, from stage 0 (persons who carry the mutation but have no detectable pathology), to stage 1 (measurable indicators of underlying pathophysiology), stage 2 (a detectable clinical phenotype), and finally to stage 3 (decline in function).
“The goal of the HDISS, which is designed for clinical research purposes, is to try to enroll individuals into clinical trials earlier rather than later, trying to get pharmaceutical companies and others to take advantage of the period prior to significant neurodegeneration occurring. Like Alzheimer’s disease and Parkinson’s disease, by the time we make a clinical diagnose significant neurodegeneration has occurred, so we really want to take advantage of the prodromal period to intervene with these potential disease-modifying therapies,” Dr. Furr Stimming said.
“At the end of the day, I suspect that we will not have just one effective disease-modifying therapy. I suspect that it will be a multifacted approach. We envision that we would hit the huntingtin protein from a few different angles. I envision that we would not only modify in some form or fashion production of the mutant huntingtin protein, but also try to influence the genetic modifiers that we think are important in somatic instability and expansion, which likely contributes to the rate of progression and symptom severity,” Dr. Furr Stimming said.
References
1. Huntington G. On Chorea. Reprinted in The Journal of Neuropsychiatry and Clinical Neurosciences. 2003;15(1):109-112. doi: 10.1176/jnp.15.1.109.
2. Kaemmerer WF and Grondin RC. Degener Neurol Neuromuscul Dis. 2019 Mar 8;9:3-17. doi: 10.2147/DNND.S163808.
3. Jimenez-Sanchez M et al. Cold Spring Harb Perspect Med. 2017 Jul 5;7(7):a024240. doi: 10.1101/cshperspect.a024240.
4. Huntington’s Disease Society of America. Overview of Huntington’s Disease. https://hdsa.org/what-is-hd/overview-of-huntingtons-disease/.
5. Beers B et al. J Neurol Neurosurg Psychiatry. 2022;93:A96. https://jnnp.bmj.com/content/93/Suppl_1/A96.1.
6. McColgan P et al. N Engl J Med. 2023 Dec 7;389(23):2203-2205. doi: 10.1056/NEJMc2300400.
7. Tabrizi SJ et al. Lancet Neurol. 2022 Jul;21(7):632-644. doi: 10.1016/S1474-4422(22)00120-X.
Much progress has been made in managing the symptoms of Huntington’s disease, but the real excitement lies in the development of disease-modifying drugs and genetic therapy.
In April 1872, The Medical and Surgical Reporter of Philadelphia published a roughly 3,000-word paper, titled “On Chorea,” by George Huntington, a 22-year-old family practice physician recently graduated from Columbia University, New York City.
“Chorea is essentially a disease of the nervous system. The name ‘chorea’ is given to the disease on account of the dancing propensities of those who are affected by it, and it is a very appropriate designation,” he wrote in the introduction.
Toward the end of the paper Dr. Huntington described a “hereditary chorea” that he had observed while on professional rounds with his father, also a physician, in towns on the eastern end of Long Island in New York.
“It is spoken of by those in whose veins the seeds of the disease are known to exist, with a kind of horror, and not at all alluded to except through dire necessity, when it is mentioned as ‘that disorder,’ ” he wrote, noting later that “I have never known a recovery or even an amelioration of symptoms in this form of chorea; when once it begins it clings to the bitter end.”1
It wasn’t until 1993 that a team of investigators identified the gene responsible for the neurodegenerative disorder we now know as Huntington’s disease.
That discovery sparked hope for better treatments and a cure, but progress over the last 31 years has been incremental. Nonetheless, recent intensive research into novel approaches for treating Huntington’s disease have considerably brightened prospects for patients and caregivers, experts say.
“This is a devastating neurodegenerative disease and in talking to families that I have had the privilege and honor of following, I hear from them that ‘in 1993 when the gene was identified and my family member — parent, grandparent, aunt, uncle — had Huntington’s, we thought that there would be a curative or disease-modifying therapy in no time,’ ” said Erin Furr Stimming, MD, FAAN, FANA professor of neurology and Memorial Hermann Endowed Chair at the McGovern Medical School at University of Texas Health Science Center in Houston.
“Here we are in 2024. I think our families are still so incredibly resilient and courageous, and they are willing and able to participate in clinical trials. Families in the Huntington’s disease community at large are really ready to have trials that do, in fact, demonstrate some evidence of slowing of disease progression. It’s an exciting time,” she said in an interview.
Repeating Nucleotides
Huntington’s disease is an autosomal dominant neurodegenerative disorder caused by an expansion of a CAG trinucleotide repeat in exon 1 of the huntingtin gene (HTT), which encodes for the huntingtin protein (HTT). The multiple repeats result in expanded expression of mutant HTT. The mutated protein disrupts normal cellular processes, alters intracellular calcium homeostasis, and interferes with gene transcription, leading to progressive degeneration of neurons, and to a hallmark Huntington’s disease triad consisting of movement disorders, cognitive decline, and mood/behavioral issues.
The number of repeats determines the severity of disease and the age of onset. In nonaffected persons the gene contains about 20 CAG repeats, but as genetics research dating from the 1990s has shown, a single HTT allele containing more than 40 CAG repeats will inevitably result in disease, whereas carriers with fewer than 36 repeats on both alleles will remain unaffected.2
The prevalence of the mutation in Western populations is estimated to be from 4 to 10 per 100,000.3
The disease usually manifests first in adults aged 30-50 years but may also occur in children or adolescents and young adults. Early symptoms often include a decline in executive function that may be noticeable to the patient’s family and friends, mood changes, and chorea.
“Because of the uncontrolled movements (chorea), a person with Huntington’s disease may lose a lot of weight without intending to, and may have trouble walking, balancing, and moving around safely. They will eventually lose the ability to work, drive, and manage tasks at home, and may qualify for disability benefits. Over time, the individual will develop difficulty with speaking and swallowing, and their movements will become slow and stiff. People with advanced Huntington’s disease need full-time care to help with their day-to-day activities, and they ultimately succumb to pneumonia, heart failure, or other complications,” according to the Huntington’s Disease Society of America.4
Managing Symptoms
say neurologists.
There are currently three medications approved for the treatment of chorea, all in the class of agents known as vesicular monoamine transporter 2 inhibitors. These agents are tetrabenazine (Xenazine, Lundbeck), deutetrabenazine (Austedo XR, Teva), and valbenazine (Ingrezza, Neurocrine Biosciences).
“These drugs can treat the chorea, but they also can help with some of the other motor features. For example, if a patient has chorea in the legs and you treat it, then maybe they’re walking will get better, or if they have chorea in the mouth and you treat the chorea, then maybe their speech and swallowing may improve,” Victor Sung, MD, professor of neurology and director of the Huntington’s Disease Clinic at the University of Alabama at Birmingham, said in an interview.
Mood and behavioral symptoms associated with Huntington’s disease – depression, anxiety, irritability, impulsivity, etc – can be managed with off-label use of antidepressants, mood stabilizers, and antipsychotic agents.
“When it comes to the cognitive symptoms, that’s a big gap where we don’t have anything that’s [Food and Drug Administration] approved for Huntington’s disease,” Dr. Sung said.
Agents used to treat Alzheimer’s disease, such as cholinesterase inhibitors and the glutamate receptor antagonist memantine, have been studied extensively for preservation of cognition in Huntington’s disease, but have not shown significant benefit.
Dr. Sung said that one promising approach to the problem of cognitive protection in Huntington’s disease is the investigational agent dalzanemdor (SAGE-718), an N-methyl-D-aspartic (NMDA) acid receptor positive allosteric modulator. The drug is in development for cognitive disorders associated with NMDA receptor dysfunction, including Huntington’s disease and Alzheimer’s disease.
In the phase 2 SURVEYOR trial, which was not powered to show efficacy of dalzanemdor over placebo, patients with Huntington’s disease reportedly tolerated the drug well, with treatment-related adverse events primarily mild or moderate in severity.
As of this writing dalzanemdor is being evaluated for efficacy, compared with placebo, in the phase 2 DIMENSION trial. The primary endpoint of this trial is a change from baseline in composite score of the Huntington’s Disease Cognitive Assessment Battery.
Disease-Modifying Therapies
As previously noted, although there is no cure for Huntington’s disease, neurology investigators are developing new strategies for delaying, stalling, or even preventing disease progression.
“There are so many different approaches, it’s hard to know where to start,” Christopher A. Ross, MD, director of the Huntington’s Disease Center at Johns Hopkins University in Baltimore, Maryland, said in an interview.
The most actively investigated approach may be huntingtin-lowering therapies, based on the supposition that mutant huntingtin protein (mHTT) is the primary toxin in Huntington’s disease.
“What you need to do is in some way lower it, and there are a number of different ways to do that: antinsense olignoclueotides, small interfering RNA, CRISPR Cas, or other gene-editing techniques, as well as gene therapy with an adenoviral vector” he said.
Gene Therapy
Dr. Ross cited as promising a phase 1/2 clinical trial of an investigational gene therapy, AMT-130 (uniQure), which consists of an adeno-associated virus vector and a gene encoding a microRNA that is designed to recognize, bind, and nonselectively lower both mHTT and wild-type HTT.
The compound is injected directly into the corpus striatum. It was demonstrated to decrease signs of Huntington’s disease in animal models, and interim data on 29 patients with Huntington’s disease followed for up to 24 months showed a statically significant, dose-dependent slowing of Huntington’s disease progression and lowering of neurofilament light protein, a marker for neuronal degeneration in Huntington’s disease, in cerebrospinal fluid (CSF).
AMT-130 targets exon 1 of the HTT gene, which appears to be an important target, Dr. Ross commented.
“The huntingtin protein is really big. The polyglutamine expansion, which is what causes the toxicity, is right at the N-terminus of exon 1, and there is increasingly good evidence that you can have an exon 1 misspliced protein product which causes the toxicity, so it may be especially important to lower Huntington by targeting exon 1,” he said.
Oral Splicing Modifier
PTC Therapeutics, based in New Jersey, is developing PTC518, an oral small molecule drug that can cross the blood-brain barrier and is reported to target mutant huntingtin protein.
The drug is a splicing modifier that promotes insertion of a premature stop codon to HTT mRNA, thereby degrading and lowering the HTT levels.5
In June 2024, the company reported that, in the phase 2a PIVOT-HD study of PTC518 in patients with Huntington’s disease, 12 months of treatment was associated with a dose-dependent lowering of mHTT in blood and CSF in an interim cohort.
“In addition, favorable trends were demonstrated on several relevant Huntington’s disease clinical assessments including Total Motor Score and Composite Unified Huntington’s Disease Rating Scale. Furthermore, following 12 months of treatment, PTC518 continues to be safe and well tolerated,” the company stated in a press release.
Antisense Oligonucleotides
Antisense oligonucleotides (ASOs) are short strands of DNA or RNA that bind to RNA sequences in faulty genes to modify production of target proteins.
One such drug, tominersen, developed jointly by Ionis and Roche, initially showed promise in a phase 1/2 trial for lowering mHTT in CSF without serious adverse events. But in a phase 3 trial, the intrathecally delivered agent was halted after an independent data monitoring committee recommended halting the trial, which Roche ended in 2021. The company reported in a letter to The New England Journal of Medicine that people in the high-dosage treatment group did measurably worse – although it remains unclear whether this was caused by excess protein lowering or an off-target effect.6 The tominersen program was the first to demonstrate that it was possible to lower HTT with an intervention, and the companies reported that they are continuing the agent’s development program.
Wave Life Sciences is developing an ASO, labeled WVE-003, designed to target a single-nucleotide polymorphism associated with the mHTT mRNA transcript within HTT. The company says that targeting the single-nucleotide polymorphism should allow lowering of expression of the mHTT will preserving wild-type HTT. This approach has the potential for therapies to prevent disease progression during the prodromal period, the company states.
Somatic Expansion
Dr. Furr Stimming and Dr. Ross both noted that there is considerable research interest into recently identified genetic modifiers that are believed to influence somatic instability, which in turn leads to somatic expansion.
“That seems to happen selectively in the neurons that are affected in Huntington’s disease. So a big puzzle for all of the neurodegenerative diseases is why are certain regions of the brain affected and other regions not? And it looks like, for the repeat expansion, this idea of somatic expansion seems to be increasingly central,” Dr. Ross said.
“The really exciting idea here is that, if somatic expansion is critical to the disease process and you could slow it down or stop it, you could go very early and potentially not just slow the progression of the disease once it starts, but conceivably even delay or possibly prevent the onset of Huntington’s disease,” he said.
Does HTT Lowering Mediate Progression?
“The next question is what does this mean clinically? Does lowering mutant huntingtin protein levels, and wild type for that matter, actually slow disease progression, which can be challenging to measure in a disease that is relatively slowly progressive?,” Dr. Furr Stimming said.
One important tool to help answer this question, she noted, is the Huntington’s Disease Integrated Staging System (HDISS), first described in 2022.7 The consensus-based system incorporates biological, clinical, and functional assessments, and characterizes patients from birth by stages, from stage 0 (persons who carry the mutation but have no detectable pathology), to stage 1 (measurable indicators of underlying pathophysiology), stage 2 (a detectable clinical phenotype), and finally to stage 3 (decline in function).
“The goal of the HDISS, which is designed for clinical research purposes, is to try to enroll individuals into clinical trials earlier rather than later, trying to get pharmaceutical companies and others to take advantage of the period prior to significant neurodegeneration occurring. Like Alzheimer’s disease and Parkinson’s disease, by the time we make a clinical diagnose significant neurodegeneration has occurred, so we really want to take advantage of the prodromal period to intervene with these potential disease-modifying therapies,” Dr. Furr Stimming said.
“At the end of the day, I suspect that we will not have just one effective disease-modifying therapy. I suspect that it will be a multifacted approach. We envision that we would hit the huntingtin protein from a few different angles. I envision that we would not only modify in some form or fashion production of the mutant huntingtin protein, but also try to influence the genetic modifiers that we think are important in somatic instability and expansion, which likely contributes to the rate of progression and symptom severity,” Dr. Furr Stimming said.
References
1. Huntington G. On Chorea. Reprinted in The Journal of Neuropsychiatry and Clinical Neurosciences. 2003;15(1):109-112. doi: 10.1176/jnp.15.1.109.
2. Kaemmerer WF and Grondin RC. Degener Neurol Neuromuscul Dis. 2019 Mar 8;9:3-17. doi: 10.2147/DNND.S163808.
3. Jimenez-Sanchez M et al. Cold Spring Harb Perspect Med. 2017 Jul 5;7(7):a024240. doi: 10.1101/cshperspect.a024240.
4. Huntington’s Disease Society of America. Overview of Huntington’s Disease. https://hdsa.org/what-is-hd/overview-of-huntingtons-disease/.
5. Beers B et al. J Neurol Neurosurg Psychiatry. 2022;93:A96. https://jnnp.bmj.com/content/93/Suppl_1/A96.1.
6. McColgan P et al. N Engl J Med. 2023 Dec 7;389(23):2203-2205. doi: 10.1056/NEJMc2300400.
7. Tabrizi SJ et al. Lancet Neurol. 2022 Jul;21(7):632-644. doi: 10.1016/S1474-4422(22)00120-X.
Much progress has been made in managing the symptoms of Huntington’s disease, but the real excitement lies in the development of disease-modifying drugs and genetic therapy.
In April 1872, The Medical and Surgical Reporter of Philadelphia published a roughly 3,000-word paper, titled “On Chorea,” by George Huntington, a 22-year-old family practice physician recently graduated from Columbia University, New York City.
“Chorea is essentially a disease of the nervous system. The name ‘chorea’ is given to the disease on account of the dancing propensities of those who are affected by it, and it is a very appropriate designation,” he wrote in the introduction.
Toward the end of the paper Dr. Huntington described a “hereditary chorea” that he had observed while on professional rounds with his father, also a physician, in towns on the eastern end of Long Island in New York.
“It is spoken of by those in whose veins the seeds of the disease are known to exist, with a kind of horror, and not at all alluded to except through dire necessity, when it is mentioned as ‘that disorder,’ ” he wrote, noting later that “I have never known a recovery or even an amelioration of symptoms in this form of chorea; when once it begins it clings to the bitter end.”1
It wasn’t until 1993 that a team of investigators identified the gene responsible for the neurodegenerative disorder we now know as Huntington’s disease.
That discovery sparked hope for better treatments and a cure, but progress over the last 31 years has been incremental. Nonetheless, recent intensive research into novel approaches for treating Huntington’s disease have considerably brightened prospects for patients and caregivers, experts say.
“This is a devastating neurodegenerative disease and in talking to families that I have had the privilege and honor of following, I hear from them that ‘in 1993 when the gene was identified and my family member — parent, grandparent, aunt, uncle — had Huntington’s, we thought that there would be a curative or disease-modifying therapy in no time,’ ” said Erin Furr Stimming, MD, FAAN, FANA professor of neurology and Memorial Hermann Endowed Chair at the McGovern Medical School at University of Texas Health Science Center in Houston.
“Here we are in 2024. I think our families are still so incredibly resilient and courageous, and they are willing and able to participate in clinical trials. Families in the Huntington’s disease community at large are really ready to have trials that do, in fact, demonstrate some evidence of slowing of disease progression. It’s an exciting time,” she said in an interview.
Repeating Nucleotides
Huntington’s disease is an autosomal dominant neurodegenerative disorder caused by an expansion of a CAG trinucleotide repeat in exon 1 of the huntingtin gene (HTT), which encodes for the huntingtin protein (HTT). The multiple repeats result in expanded expression of mutant HTT. The mutated protein disrupts normal cellular processes, alters intracellular calcium homeostasis, and interferes with gene transcription, leading to progressive degeneration of neurons, and to a hallmark Huntington’s disease triad consisting of movement disorders, cognitive decline, and mood/behavioral issues.
The number of repeats determines the severity of disease and the age of onset. In nonaffected persons the gene contains about 20 CAG repeats, but as genetics research dating from the 1990s has shown, a single HTT allele containing more than 40 CAG repeats will inevitably result in disease, whereas carriers with fewer than 36 repeats on both alleles will remain unaffected.2
The prevalence of the mutation in Western populations is estimated to be from 4 to 10 per 100,000.3
The disease usually manifests first in adults aged 30-50 years but may also occur in children or adolescents and young adults. Early symptoms often include a decline in executive function that may be noticeable to the patient’s family and friends, mood changes, and chorea.
“Because of the uncontrolled movements (chorea), a person with Huntington’s disease may lose a lot of weight without intending to, and may have trouble walking, balancing, and moving around safely. They will eventually lose the ability to work, drive, and manage tasks at home, and may qualify for disability benefits. Over time, the individual will develop difficulty with speaking and swallowing, and their movements will become slow and stiff. People with advanced Huntington’s disease need full-time care to help with their day-to-day activities, and they ultimately succumb to pneumonia, heart failure, or other complications,” according to the Huntington’s Disease Society of America.4
Managing Symptoms
say neurologists.
There are currently three medications approved for the treatment of chorea, all in the class of agents known as vesicular monoamine transporter 2 inhibitors. These agents are tetrabenazine (Xenazine, Lundbeck), deutetrabenazine (Austedo XR, Teva), and valbenazine (Ingrezza, Neurocrine Biosciences).
“These drugs can treat the chorea, but they also can help with some of the other motor features. For example, if a patient has chorea in the legs and you treat it, then maybe they’re walking will get better, or if they have chorea in the mouth and you treat the chorea, then maybe their speech and swallowing may improve,” Victor Sung, MD, professor of neurology and director of the Huntington’s Disease Clinic at the University of Alabama at Birmingham, said in an interview.
Mood and behavioral symptoms associated with Huntington’s disease – depression, anxiety, irritability, impulsivity, etc – can be managed with off-label use of antidepressants, mood stabilizers, and antipsychotic agents.
“When it comes to the cognitive symptoms, that’s a big gap where we don’t have anything that’s [Food and Drug Administration] approved for Huntington’s disease,” Dr. Sung said.
Agents used to treat Alzheimer’s disease, such as cholinesterase inhibitors and the glutamate receptor antagonist memantine, have been studied extensively for preservation of cognition in Huntington’s disease, but have not shown significant benefit.
Dr. Sung said that one promising approach to the problem of cognitive protection in Huntington’s disease is the investigational agent dalzanemdor (SAGE-718), an N-methyl-D-aspartic (NMDA) acid receptor positive allosteric modulator. The drug is in development for cognitive disorders associated with NMDA receptor dysfunction, including Huntington’s disease and Alzheimer’s disease.
In the phase 2 SURVEYOR trial, which was not powered to show efficacy of dalzanemdor over placebo, patients with Huntington’s disease reportedly tolerated the drug well, with treatment-related adverse events primarily mild or moderate in severity.
As of this writing dalzanemdor is being evaluated for efficacy, compared with placebo, in the phase 2 DIMENSION trial. The primary endpoint of this trial is a change from baseline in composite score of the Huntington’s Disease Cognitive Assessment Battery.
Disease-Modifying Therapies
As previously noted, although there is no cure for Huntington’s disease, neurology investigators are developing new strategies for delaying, stalling, or even preventing disease progression.
“There are so many different approaches, it’s hard to know where to start,” Christopher A. Ross, MD, director of the Huntington’s Disease Center at Johns Hopkins University in Baltimore, Maryland, said in an interview.
The most actively investigated approach may be huntingtin-lowering therapies, based on the supposition that mutant huntingtin protein (mHTT) is the primary toxin in Huntington’s disease.
“What you need to do is in some way lower it, and there are a number of different ways to do that: antinsense olignoclueotides, small interfering RNA, CRISPR Cas, or other gene-editing techniques, as well as gene therapy with an adenoviral vector” he said.
Gene Therapy
Dr. Ross cited as promising a phase 1/2 clinical trial of an investigational gene therapy, AMT-130 (uniQure), which consists of an adeno-associated virus vector and a gene encoding a microRNA that is designed to recognize, bind, and nonselectively lower both mHTT and wild-type HTT.
The compound is injected directly into the corpus striatum. It was demonstrated to decrease signs of Huntington’s disease in animal models, and interim data on 29 patients with Huntington’s disease followed for up to 24 months showed a statically significant, dose-dependent slowing of Huntington’s disease progression and lowering of neurofilament light protein, a marker for neuronal degeneration in Huntington’s disease, in cerebrospinal fluid (CSF).
AMT-130 targets exon 1 of the HTT gene, which appears to be an important target, Dr. Ross commented.
“The huntingtin protein is really big. The polyglutamine expansion, which is what causes the toxicity, is right at the N-terminus of exon 1, and there is increasingly good evidence that you can have an exon 1 misspliced protein product which causes the toxicity, so it may be especially important to lower Huntington by targeting exon 1,” he said.
Oral Splicing Modifier
PTC Therapeutics, based in New Jersey, is developing PTC518, an oral small molecule drug that can cross the blood-brain barrier and is reported to target mutant huntingtin protein.
The drug is a splicing modifier that promotes insertion of a premature stop codon to HTT mRNA, thereby degrading and lowering the HTT levels.5
In June 2024, the company reported that, in the phase 2a PIVOT-HD study of PTC518 in patients with Huntington’s disease, 12 months of treatment was associated with a dose-dependent lowering of mHTT in blood and CSF in an interim cohort.
“In addition, favorable trends were demonstrated on several relevant Huntington’s disease clinical assessments including Total Motor Score and Composite Unified Huntington’s Disease Rating Scale. Furthermore, following 12 months of treatment, PTC518 continues to be safe and well tolerated,” the company stated in a press release.
Antisense Oligonucleotides
Antisense oligonucleotides (ASOs) are short strands of DNA or RNA that bind to RNA sequences in faulty genes to modify production of target proteins.
One such drug, tominersen, developed jointly by Ionis and Roche, initially showed promise in a phase 1/2 trial for lowering mHTT in CSF without serious adverse events. But in a phase 3 trial, the intrathecally delivered agent was halted after an independent data monitoring committee recommended halting the trial, which Roche ended in 2021. The company reported in a letter to The New England Journal of Medicine that people in the high-dosage treatment group did measurably worse – although it remains unclear whether this was caused by excess protein lowering or an off-target effect.6 The tominersen program was the first to demonstrate that it was possible to lower HTT with an intervention, and the companies reported that they are continuing the agent’s development program.
Wave Life Sciences is developing an ASO, labeled WVE-003, designed to target a single-nucleotide polymorphism associated with the mHTT mRNA transcript within HTT. The company says that targeting the single-nucleotide polymorphism should allow lowering of expression of the mHTT will preserving wild-type HTT. This approach has the potential for therapies to prevent disease progression during the prodromal period, the company states.
Somatic Expansion
Dr. Furr Stimming and Dr. Ross both noted that there is considerable research interest into recently identified genetic modifiers that are believed to influence somatic instability, which in turn leads to somatic expansion.
“That seems to happen selectively in the neurons that are affected in Huntington’s disease. So a big puzzle for all of the neurodegenerative diseases is why are certain regions of the brain affected and other regions not? And it looks like, for the repeat expansion, this idea of somatic expansion seems to be increasingly central,” Dr. Ross said.
“The really exciting idea here is that, if somatic expansion is critical to the disease process and you could slow it down or stop it, you could go very early and potentially not just slow the progression of the disease once it starts, but conceivably even delay or possibly prevent the onset of Huntington’s disease,” he said.
Does HTT Lowering Mediate Progression?
“The next question is what does this mean clinically? Does lowering mutant huntingtin protein levels, and wild type for that matter, actually slow disease progression, which can be challenging to measure in a disease that is relatively slowly progressive?,” Dr. Furr Stimming said.
One important tool to help answer this question, she noted, is the Huntington’s Disease Integrated Staging System (HDISS), first described in 2022.7 The consensus-based system incorporates biological, clinical, and functional assessments, and characterizes patients from birth by stages, from stage 0 (persons who carry the mutation but have no detectable pathology), to stage 1 (measurable indicators of underlying pathophysiology), stage 2 (a detectable clinical phenotype), and finally to stage 3 (decline in function).
“The goal of the HDISS, which is designed for clinical research purposes, is to try to enroll individuals into clinical trials earlier rather than later, trying to get pharmaceutical companies and others to take advantage of the period prior to significant neurodegeneration occurring. Like Alzheimer’s disease and Parkinson’s disease, by the time we make a clinical diagnose significant neurodegeneration has occurred, so we really want to take advantage of the prodromal period to intervene with these potential disease-modifying therapies,” Dr. Furr Stimming said.
“At the end of the day, I suspect that we will not have just one effective disease-modifying therapy. I suspect that it will be a multifacted approach. We envision that we would hit the huntingtin protein from a few different angles. I envision that we would not only modify in some form or fashion production of the mutant huntingtin protein, but also try to influence the genetic modifiers that we think are important in somatic instability and expansion, which likely contributes to the rate of progression and symptom severity,” Dr. Furr Stimming said.
References
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2. Kaemmerer WF and Grondin RC. Degener Neurol Neuromuscul Dis. 2019 Mar 8;9:3-17. doi: 10.2147/DNND.S163808.
3. Jimenez-Sanchez M et al. Cold Spring Harb Perspect Med. 2017 Jul 5;7(7):a024240. doi: 10.1101/cshperspect.a024240.
4. Huntington’s Disease Society of America. Overview of Huntington’s Disease. https://hdsa.org/what-is-hd/overview-of-huntingtons-disease/.
5. Beers B et al. J Neurol Neurosurg Psychiatry. 2022;93:A96. https://jnnp.bmj.com/content/93/Suppl_1/A96.1.
6. McColgan P et al. N Engl J Med. 2023 Dec 7;389(23):2203-2205. doi: 10.1056/NEJMc2300400.
7. Tabrizi SJ et al. Lancet Neurol. 2022 Jul;21(7):632-644. doi: 10.1016/S1474-4422(22)00120-X.