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The past decade has been a contradictory one for research on Huntington’s disease, marked by breakthroughs in the biology and genetics of this fatal neurodegenerative disease and painful disappointments in trials of novel therapies.
What is Huntington’s disease?
Huntington’s disease is caused by a trinucleotide repeat mutation in the huntingtin gene (HTT) and follows an autosomal dominant pattern of inheritance. In people with more than 39 copies of this CAG repeat tract expansion, the HTT protein misfolds to become toxic, with more repeats linked to earlier disease onset and a more severe course.
Huntington’s disease causes loss of neurons in the striatum and disrupts the cortical-striatal-thalamic pathway, a brain circuit that governs movement. Although behavioral symptoms can emerge earlier, signature symptoms – chorea, dystonia, and cognitive abnormalities – usually present at midlife and progress until the patient’s death.
Huntington’s disease affects an estimated 30,000 people in the United States, and an estimated 10-12 people for every 100,000 worldwide – making it rare enough that neurologists who do not specialize in movement disorders might never treat a Huntington’s patient. Yet Huntington’s disease is sufficiently prevalent to attract robust research interest and sustain large registries, which have led to remarkable findings with implications not just for Huntington’s disease but for other diseases as well.
Right now, the only Food and Drug Administration–approved treatments for Huntington’s disease are symptomatic therapies to help temper disturbances of movement, sleep, and emotions. There are two major avenues of investigation into Huntington’s disease modification:
Reduce levels of mutant HTT protein, whether through small molecules, gene therapies, or antisense oligonucleotides (ASOs) that modulate RNA processing. In March 2021, Roche announced the suspension of its phase 3 trial of tominersen, an ASO.1 Trials of other protein-lowering agents were canceled for lack of target engagement or over safety concerns, in 2021 and 2022, although this approach is still considered viable.
Modify the length of CAG repeats, which involves a more recently encountered mechanism in Huntington’s disease. The strategy is at the preclinical stage. In 2015, a group of scientists reported the game-changing discovery that a large number of genes, associated with some of the same DNA-mismatch repair pathways implicated in cancer, can modify the length of CAG repeats in cells. This gave rise to a new set of therapeutic targets, now being explored.
Neurology Reviews 2023 Rare Neurological Disease Special Report spoke with two frequently collaborating researchers at the forefront of Huntington’s disease science – Cristina Sampaio, MD, PhD, chief medical officer of CHDI Management, Princeton, N.J., and Sarah Tabrizi, MD, PhD, from University College London – about lessons learned from the past several years of Huntington’s disease drug research.
The CHDI Foundation, a nonprofit research organization, was founded in 2003 to facilitate development of Huntington’s disease therapies. Its clinical research platform, Enroll-HD, includes a global registry of some 28,000 patients and a biobank to facilitate biomarker discovery and validation. Dr. Tabrizi’s lab explores Huntington’s disease drug targets in both HTT and DNA mismatch repair, and led two CHDI-funded observational studies, TRACK-HD and TrackOn-HD, to characterize disease progression in people with Huntington’s disease. In 2022, Dr. Tabrizi and Dr. Sampaio were coauthors of a comprehensive review of Huntington’s disease drug development and published a new disease-staging system to help enable trials in presymptomatic Huntington’s disease.
“The story of Huntington’s therapeutics is very informative,” Dr. Sampaio said. “Understanding these mechanisms is relevant for any neurologist – not only for Huntington’s but because they represent a prototype development for a big group of therapies and make us better equipped to think about everything else that is happening in neurology. They’re giving us an understanding of where neurology is going.”
Tackling a tricky protein
Most Huntington’s disease research has focused on ways to attack or lower mutant HTT protein. But HTT has proven a tricky target: HTT is a large protein, present in all cells, and known to interact with more than 100 genes. Healthy HTT is critical to fetal development, but its functions in the adult body remain something of a mystery. Almost all people with Huntington’s disease have both wild-type and mutant HTT.
Tominersen, the investigative ASO developed by Roche, works to block translation of the HTT message, leading to a reduction in both healthy and mutant HTT protein. It is delivered by lumbar injection to reach the brain. Upon halting its phase 3 trial of tominersen in 2021, Roche reported 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. The tominersen program was the first to clearly show that it is possible to lower HTT with an intervention – a critical first step in the development of this class of drugs.
“I think the problem with the trial was the aggressive loading doses plus exposure-related toxicity,” Dr. Tabrizi said. “Whether that exposure-related toxicity was related to too much wild-type HTT lowering or the proinflammatory effects of the ASO, you can’t yet disentangle.” Roche has not given up: The company is now seeking to test lower dosages of tominersen on a younger subgroup of patients who have fewer CAG repeats, in whom a benefit of protein lowering might be more clearly seen.
Small molecules and gene therapies have also been developed to reduce mutant HTT, although most, as is the case with tominersen, will also reduce healthy protein.
“There is a long and complex debate about how much [lowering] is too much and how much is enough,” Dr. Sampaio said. “And this is a problem that has not been solved.”
Allele-specific therapy. A different class of investigative drugs, called allele-specific therapies, target only mutant HTT, sparing healthy protein. The drugs are tailored to genetic markers, or single-nucleotide polymorphisms (SNPs), that are present in different Huntington’s disease populations worldwide. Because treatments based on SNPs are highly tailored, “you need a new drug for each SNP to cover the global Huntington’s disease population,” Dr. Sampaio said. “This presents challenges from a regulatory perspective, as each drug would have to be evaluated separately.”
Two SNP-based therapies failed clinical trials in 2021, when they did not engage their targets.2 A third trial succeeded in lowering mutant HTT while preserving healthy protein and is being evaluated further in the clinic.2
Other strategies have yielded disappointing or mixed results:
A trial of branaplam, a small molecule, was stopped late in 2022 after patients developed peripheral neuropathy.3 Novartis, the drug’s manufacturer, said it would no longer investigate branaplam for Huntington’s disease.
Months earlier, in August 2022, a trial of a gene therapy to lower HTT protein – injected directly into the striatum of the brain – was halted because of adverse events in its high-dosage arm but has since resumed, with some changes to protocol.4
In neither case was excess protein-lowering thought to be the cause of safety problems.
DNA repair emerges as a promising target
Scientists have understood, since the 1990s, that the number of excess CAG repeats measured in a blood test is not the sole predictor of the onset of motor symptoms or rate of progression of Huntington’s disease.
Since the early 2000s, researchers have also known that the number of CAG repeats in cells is unstable, both in different tissues and cell types, and over time. People with Huntington’s disease turned out to be genetic mosaics, with varying, changing lengths of CAG repeats in cells. Repeats increase as a person ages, most drastically in the spiny medium neurons of the brain.
The process by which CAG repetitions grow in cells, known as somatic instability, remained poorly understood and little investigated until 2015, when a genomewide association study revealed previously unknown mechanisms.5 As it turns out, genes involved in the growth of CAG repeats are related to the DNA mismatch repair pathway, which is also important in cancer.
DNA mismatch repair refers to a complex housekeeping system, involving multiple genes and enzymes, that is fundamental to the functioning of the body as genes are continuously being translated to form proteins. Mismatch repair becomes increasingly error-prone with age: Mistakes that are not repaired become mutations, some of which are irrelevant and others that can be deleterious and lead to cancer.
In Huntington’s disease, enzymes involved in repairing DNA are the same ones that can erroneously add CAG repeats to HTT. A person with Huntington’s disease inherits what can be considered a “dyslexic” DNA repair system, Dr. Sampaio said, that misreads its template and keeps adding CAGs.
After the 2015 genomewide association study, “the DNA mismatch repair pathway became hugely important in Huntington’s disease research, and there is a lot of attention being paid now to its components. The idea is that, if we can intervene in this process, we might stop the somatic instability, the growing of the CAG repetitions, and ameliorate the progression of the disease,” Dr. Sampaio said.
In 2017 Dr. Tabrizi’s team reported that the mismatch repair gene MSH-3 was as a key driver of CAG repeats in people with Huntington’s disease.6 “I’m working really closely now with DNA repair scientists who’ve been working in cancer for 20 years. Cancer and repeat expansion diseases have really come together,” Dr. Tabrizi said.
At CHDI’s April 2023 therapeutics conference in Dubrovnik, Croatia, scientists presented findings on how to target MSH-3 and other mechanisms that underlie somatic instability.7 (Several drug companies are working on small molecules, ASOs, and other ways to inhibit MSH-3.) Researchers also presented extensively on protein lowering. The two treatment strategies are compatible for Huntington’s disease, Dr. Tabrizi said.
“I think the best way to approach Huntington’s is to target the somatic CAG repeat expansion by inhibiting MSH-3 in some way, and also target HTT lowering – but targeting it at the DNA level, as opposed to clearing the protein,” Dr. Tabrizi said. DNA-centered approaches in preclinical testing include CRISPR gene editing to inactivate mutant HTT and zinc finger proteins that allow selective targeting of DNA to reduce mutant HTT.
Recent findings on the mismatch repair pathway in Huntington’s disease have direct implications for other rare neurologic diseases caused by triplet repeat mutations, including myotonic dystrophy and cerebellar ataxias.
“There is very strong basic fundamental research in Huntington’s disease that doesn’t exist for every disease,” Dr. Sampaio said. “The fact that it is monogenic, and an adult disease that progresses relatively slowly, has made it a good disease to study, a kind of model.”
Huntington’s disease research has also generated research strategies of value in neurodegenerative diseases, such as Alzheimer’s and Parkinson’s. It provided key insights about neurofilament light, a biomarker of neuronal damage, and about the ASO drug class, which is being investigated for its utility treating in a range of diseases.
Previously, Huntington’s disease trial cohorts and registries focused on patients with late symptomatic disease. However, researchers are now pivoting to patients with less-severe disease and to preclinical mutation carriers. “We now know you have to treat early,” Dr. Tabrizi said. “This has implications for the whole field.”
Dr. Sampaio disclosed that she is an employee of CHDI Management, the administrative arm of the CHDI foundation. Dr. Tabrizi disclosed serving as a consultant to Alnylam Pharmaceuticals, Annexon, Ascidian Therapeutics, Arrowhead Pharmaceuticals, Atalanta Therapeutics, Design Therapeutics, F. Hoffmann-La Roche, HCD Economics, IQVIA, Iris Medicine, Latus Bio, LifeEdit, Novartis, Pfizer, Prilenia Therapeutics, PTC Therapeutics, Rgenta Therapeutics, Takeda Pharmaceuticals, uniQure, and Vertex Pharmaceuticals.
References
1. Genentech. Genentech Provides Update on Tominersen Program in Manifest Huntington’s Disease. https://www.gene.com/media/press-releases/14902/2021-03-22/genentech-provides-update-on-tominersen-.
2. Wave Life Sciences. Defining a new era of oligonucleotides. https://ir.wavelifesciences.com/news-releases/news-release-details/wave-life-sciences-announces-positive-update-phase-1b2a-select.
3. Novartis. Community update: Status of VIBRANT-HD, the study of branaplam/LMI070 in Huntington’s disease. https://hdsa.org/wp-content/uploads/2022/08/Novartis-FINAL-Community-Letter-8-24-22.pdf.
4. UniQure. Second Quarter 2022 Financial Results. https://uniqure.gcs-web.com/node/10856/pdf.
5. Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium. Cell. 2015 Jul 30;162(3):516-26. doi: 10.1016/j.cell.2015.07.003.
6. Moss DJH et al. Lancet Neurol. 2017 Sep;16(9):701-11. doi: 10.1016/S1474-4422(17)30161-8.
7. CHDI Foundation. Postcard from Dubrovnik 2023. https://chdifoundation.org/postcard-from-dubrovnik-2023/.
The past decade has been a contradictory one for research on Huntington’s disease, marked by breakthroughs in the biology and genetics of this fatal neurodegenerative disease and painful disappointments in trials of novel therapies.
What is Huntington’s disease?
Huntington’s disease is caused by a trinucleotide repeat mutation in the huntingtin gene (HTT) and follows an autosomal dominant pattern of inheritance. In people with more than 39 copies of this CAG repeat tract expansion, the HTT protein misfolds to become toxic, with more repeats linked to earlier disease onset and a more severe course.
Huntington’s disease causes loss of neurons in the striatum and disrupts the cortical-striatal-thalamic pathway, a brain circuit that governs movement. Although behavioral symptoms can emerge earlier, signature symptoms – chorea, dystonia, and cognitive abnormalities – usually present at midlife and progress until the patient’s death.
Huntington’s disease affects an estimated 30,000 people in the United States, and an estimated 10-12 people for every 100,000 worldwide – making it rare enough that neurologists who do not specialize in movement disorders might never treat a Huntington’s patient. Yet Huntington’s disease is sufficiently prevalent to attract robust research interest and sustain large registries, which have led to remarkable findings with implications not just for Huntington’s disease but for other diseases as well.
Right now, the only Food and Drug Administration–approved treatments for Huntington’s disease are symptomatic therapies to help temper disturbances of movement, sleep, and emotions. There are two major avenues of investigation into Huntington’s disease modification:
Reduce levels of mutant HTT protein, whether through small molecules, gene therapies, or antisense oligonucleotides (ASOs) that modulate RNA processing. In March 2021, Roche announced the suspension of its phase 3 trial of tominersen, an ASO.1 Trials of other protein-lowering agents were canceled for lack of target engagement or over safety concerns, in 2021 and 2022, although this approach is still considered viable.
Modify the length of CAG repeats, which involves a more recently encountered mechanism in Huntington’s disease. The strategy is at the preclinical stage. In 2015, a group of scientists reported the game-changing discovery that a large number of genes, associated with some of the same DNA-mismatch repair pathways implicated in cancer, can modify the length of CAG repeats in cells. This gave rise to a new set of therapeutic targets, now being explored.
Neurology Reviews 2023 Rare Neurological Disease Special Report spoke with two frequently collaborating researchers at the forefront of Huntington’s disease science – Cristina Sampaio, MD, PhD, chief medical officer of CHDI Management, Princeton, N.J., and Sarah Tabrizi, MD, PhD, from University College London – about lessons learned from the past several years of Huntington’s disease drug research.
The CHDI Foundation, a nonprofit research organization, was founded in 2003 to facilitate development of Huntington’s disease therapies. Its clinical research platform, Enroll-HD, includes a global registry of some 28,000 patients and a biobank to facilitate biomarker discovery and validation. Dr. Tabrizi’s lab explores Huntington’s disease drug targets in both HTT and DNA mismatch repair, and led two CHDI-funded observational studies, TRACK-HD and TrackOn-HD, to characterize disease progression in people with Huntington’s disease. In 2022, Dr. Tabrizi and Dr. Sampaio were coauthors of a comprehensive review of Huntington’s disease drug development and published a new disease-staging system to help enable trials in presymptomatic Huntington’s disease.
“The story of Huntington’s therapeutics is very informative,” Dr. Sampaio said. “Understanding these mechanisms is relevant for any neurologist – not only for Huntington’s but because they represent a prototype development for a big group of therapies and make us better equipped to think about everything else that is happening in neurology. They’re giving us an understanding of where neurology is going.”
Tackling a tricky protein
Most Huntington’s disease research has focused on ways to attack or lower mutant HTT protein. But HTT has proven a tricky target: HTT is a large protein, present in all cells, and known to interact with more than 100 genes. Healthy HTT is critical to fetal development, but its functions in the adult body remain something of a mystery. Almost all people with Huntington’s disease have both wild-type and mutant HTT.
Tominersen, the investigative ASO developed by Roche, works to block translation of the HTT message, leading to a reduction in both healthy and mutant HTT protein. It is delivered by lumbar injection to reach the brain. Upon halting its phase 3 trial of tominersen in 2021, Roche reported 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. The tominersen program was the first to clearly show that it is possible to lower HTT with an intervention – a critical first step in the development of this class of drugs.
“I think the problem with the trial was the aggressive loading doses plus exposure-related toxicity,” Dr. Tabrizi said. “Whether that exposure-related toxicity was related to too much wild-type HTT lowering or the proinflammatory effects of the ASO, you can’t yet disentangle.” Roche has not given up: The company is now seeking to test lower dosages of tominersen on a younger subgroup of patients who have fewer CAG repeats, in whom a benefit of protein lowering might be more clearly seen.
Small molecules and gene therapies have also been developed to reduce mutant HTT, although most, as is the case with tominersen, will also reduce healthy protein.
“There is a long and complex debate about how much [lowering] is too much and how much is enough,” Dr. Sampaio said. “And this is a problem that has not been solved.”
Allele-specific therapy. A different class of investigative drugs, called allele-specific therapies, target only mutant HTT, sparing healthy protein. The drugs are tailored to genetic markers, or single-nucleotide polymorphisms (SNPs), that are present in different Huntington’s disease populations worldwide. Because treatments based on SNPs are highly tailored, “you need a new drug for each SNP to cover the global Huntington’s disease population,” Dr. Sampaio said. “This presents challenges from a regulatory perspective, as each drug would have to be evaluated separately.”
Two SNP-based therapies failed clinical trials in 2021, when they did not engage their targets.2 A third trial succeeded in lowering mutant HTT while preserving healthy protein and is being evaluated further in the clinic.2
Other strategies have yielded disappointing or mixed results:
A trial of branaplam, a small molecule, was stopped late in 2022 after patients developed peripheral neuropathy.3 Novartis, the drug’s manufacturer, said it would no longer investigate branaplam for Huntington’s disease.
Months earlier, in August 2022, a trial of a gene therapy to lower HTT protein – injected directly into the striatum of the brain – was halted because of adverse events in its high-dosage arm but has since resumed, with some changes to protocol.4
In neither case was excess protein-lowering thought to be the cause of safety problems.
DNA repair emerges as a promising target
Scientists have understood, since the 1990s, that the number of excess CAG repeats measured in a blood test is not the sole predictor of the onset of motor symptoms or rate of progression of Huntington’s disease.
Since the early 2000s, researchers have also known that the number of CAG repeats in cells is unstable, both in different tissues and cell types, and over time. People with Huntington’s disease turned out to be genetic mosaics, with varying, changing lengths of CAG repeats in cells. Repeats increase as a person ages, most drastically in the spiny medium neurons of the brain.
The process by which CAG repetitions grow in cells, known as somatic instability, remained poorly understood and little investigated until 2015, when a genomewide association study revealed previously unknown mechanisms.5 As it turns out, genes involved in the growth of CAG repeats are related to the DNA mismatch repair pathway, which is also important in cancer.
DNA mismatch repair refers to a complex housekeeping system, involving multiple genes and enzymes, that is fundamental to the functioning of the body as genes are continuously being translated to form proteins. Mismatch repair becomes increasingly error-prone with age: Mistakes that are not repaired become mutations, some of which are irrelevant and others that can be deleterious and lead to cancer.
In Huntington’s disease, enzymes involved in repairing DNA are the same ones that can erroneously add CAG repeats to HTT. A person with Huntington’s disease inherits what can be considered a “dyslexic” DNA repair system, Dr. Sampaio said, that misreads its template and keeps adding CAGs.
After the 2015 genomewide association study, “the DNA mismatch repair pathway became hugely important in Huntington’s disease research, and there is a lot of attention being paid now to its components. The idea is that, if we can intervene in this process, we might stop the somatic instability, the growing of the CAG repetitions, and ameliorate the progression of the disease,” Dr. Sampaio said.
In 2017 Dr. Tabrizi’s team reported that the mismatch repair gene MSH-3 was as a key driver of CAG repeats in people with Huntington’s disease.6 “I’m working really closely now with DNA repair scientists who’ve been working in cancer for 20 years. Cancer and repeat expansion diseases have really come together,” Dr. Tabrizi said.
At CHDI’s April 2023 therapeutics conference in Dubrovnik, Croatia, scientists presented findings on how to target MSH-3 and other mechanisms that underlie somatic instability.7 (Several drug companies are working on small molecules, ASOs, and other ways to inhibit MSH-3.) Researchers also presented extensively on protein lowering. The two treatment strategies are compatible for Huntington’s disease, Dr. Tabrizi said.
“I think the best way to approach Huntington’s is to target the somatic CAG repeat expansion by inhibiting MSH-3 in some way, and also target HTT lowering – but targeting it at the DNA level, as opposed to clearing the protein,” Dr. Tabrizi said. DNA-centered approaches in preclinical testing include CRISPR gene editing to inactivate mutant HTT and zinc finger proteins that allow selective targeting of DNA to reduce mutant HTT.
Recent findings on the mismatch repair pathway in Huntington’s disease have direct implications for other rare neurologic diseases caused by triplet repeat mutations, including myotonic dystrophy and cerebellar ataxias.
“There is very strong basic fundamental research in Huntington’s disease that doesn’t exist for every disease,” Dr. Sampaio said. “The fact that it is monogenic, and an adult disease that progresses relatively slowly, has made it a good disease to study, a kind of model.”
Huntington’s disease research has also generated research strategies of value in neurodegenerative diseases, such as Alzheimer’s and Parkinson’s. It provided key insights about neurofilament light, a biomarker of neuronal damage, and about the ASO drug class, which is being investigated for its utility treating in a range of diseases.
Previously, Huntington’s disease trial cohorts and registries focused on patients with late symptomatic disease. However, researchers are now pivoting to patients with less-severe disease and to preclinical mutation carriers. “We now know you have to treat early,” Dr. Tabrizi said. “This has implications for the whole field.”
Dr. Sampaio disclosed that she is an employee of CHDI Management, the administrative arm of the CHDI foundation. Dr. Tabrizi disclosed serving as a consultant to Alnylam Pharmaceuticals, Annexon, Ascidian Therapeutics, Arrowhead Pharmaceuticals, Atalanta Therapeutics, Design Therapeutics, F. Hoffmann-La Roche, HCD Economics, IQVIA, Iris Medicine, Latus Bio, LifeEdit, Novartis, Pfizer, Prilenia Therapeutics, PTC Therapeutics, Rgenta Therapeutics, Takeda Pharmaceuticals, uniQure, and Vertex Pharmaceuticals.
References
1. Genentech. Genentech Provides Update on Tominersen Program in Manifest Huntington’s Disease. https://www.gene.com/media/press-releases/14902/2021-03-22/genentech-provides-update-on-tominersen-.
2. Wave Life Sciences. Defining a new era of oligonucleotides. https://ir.wavelifesciences.com/news-releases/news-release-details/wave-life-sciences-announces-positive-update-phase-1b2a-select.
3. Novartis. Community update: Status of VIBRANT-HD, the study of branaplam/LMI070 in Huntington’s disease. https://hdsa.org/wp-content/uploads/2022/08/Novartis-FINAL-Community-Letter-8-24-22.pdf.
4. UniQure. Second Quarter 2022 Financial Results. https://uniqure.gcs-web.com/node/10856/pdf.
5. Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium. Cell. 2015 Jul 30;162(3):516-26. doi: 10.1016/j.cell.2015.07.003.
6. Moss DJH et al. Lancet Neurol. 2017 Sep;16(9):701-11. doi: 10.1016/S1474-4422(17)30161-8.
7. CHDI Foundation. Postcard from Dubrovnik 2023. https://chdifoundation.org/postcard-from-dubrovnik-2023/.
The past decade has been a contradictory one for research on Huntington’s disease, marked by breakthroughs in the biology and genetics of this fatal neurodegenerative disease and painful disappointments in trials of novel therapies.
What is Huntington’s disease?
Huntington’s disease is caused by a trinucleotide repeat mutation in the huntingtin gene (HTT) and follows an autosomal dominant pattern of inheritance. In people with more than 39 copies of this CAG repeat tract expansion, the HTT protein misfolds to become toxic, with more repeats linked to earlier disease onset and a more severe course.
Huntington’s disease causes loss of neurons in the striatum and disrupts the cortical-striatal-thalamic pathway, a brain circuit that governs movement. Although behavioral symptoms can emerge earlier, signature symptoms – chorea, dystonia, and cognitive abnormalities – usually present at midlife and progress until the patient’s death.
Huntington’s disease affects an estimated 30,000 people in the United States, and an estimated 10-12 people for every 100,000 worldwide – making it rare enough that neurologists who do not specialize in movement disorders might never treat a Huntington’s patient. Yet Huntington’s disease is sufficiently prevalent to attract robust research interest and sustain large registries, which have led to remarkable findings with implications not just for Huntington’s disease but for other diseases as well.
Right now, the only Food and Drug Administration–approved treatments for Huntington’s disease are symptomatic therapies to help temper disturbances of movement, sleep, and emotions. There are two major avenues of investigation into Huntington’s disease modification:
Reduce levels of mutant HTT protein, whether through small molecules, gene therapies, or antisense oligonucleotides (ASOs) that modulate RNA processing. In March 2021, Roche announced the suspension of its phase 3 trial of tominersen, an ASO.1 Trials of other protein-lowering agents were canceled for lack of target engagement or over safety concerns, in 2021 and 2022, although this approach is still considered viable.
Modify the length of CAG repeats, which involves a more recently encountered mechanism in Huntington’s disease. The strategy is at the preclinical stage. In 2015, a group of scientists reported the game-changing discovery that a large number of genes, associated with some of the same DNA-mismatch repair pathways implicated in cancer, can modify the length of CAG repeats in cells. This gave rise to a new set of therapeutic targets, now being explored.
Neurology Reviews 2023 Rare Neurological Disease Special Report spoke with two frequently collaborating researchers at the forefront of Huntington’s disease science – Cristina Sampaio, MD, PhD, chief medical officer of CHDI Management, Princeton, N.J., and Sarah Tabrizi, MD, PhD, from University College London – about lessons learned from the past several years of Huntington’s disease drug research.
The CHDI Foundation, a nonprofit research organization, was founded in 2003 to facilitate development of Huntington’s disease therapies. Its clinical research platform, Enroll-HD, includes a global registry of some 28,000 patients and a biobank to facilitate biomarker discovery and validation. Dr. Tabrizi’s lab explores Huntington’s disease drug targets in both HTT and DNA mismatch repair, and led two CHDI-funded observational studies, TRACK-HD and TrackOn-HD, to characterize disease progression in people with Huntington’s disease. In 2022, Dr. Tabrizi and Dr. Sampaio were coauthors of a comprehensive review of Huntington’s disease drug development and published a new disease-staging system to help enable trials in presymptomatic Huntington’s disease.
“The story of Huntington’s therapeutics is very informative,” Dr. Sampaio said. “Understanding these mechanisms is relevant for any neurologist – not only for Huntington’s but because they represent a prototype development for a big group of therapies and make us better equipped to think about everything else that is happening in neurology. They’re giving us an understanding of where neurology is going.”
Tackling a tricky protein
Most Huntington’s disease research has focused on ways to attack or lower mutant HTT protein. But HTT has proven a tricky target: HTT is a large protein, present in all cells, and known to interact with more than 100 genes. Healthy HTT is critical to fetal development, but its functions in the adult body remain something of a mystery. Almost all people with Huntington’s disease have both wild-type and mutant HTT.
Tominersen, the investigative ASO developed by Roche, works to block translation of the HTT message, leading to a reduction in both healthy and mutant HTT protein. It is delivered by lumbar injection to reach the brain. Upon halting its phase 3 trial of tominersen in 2021, Roche reported 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. The tominersen program was the first to clearly show that it is possible to lower HTT with an intervention – a critical first step in the development of this class of drugs.
“I think the problem with the trial was the aggressive loading doses plus exposure-related toxicity,” Dr. Tabrizi said. “Whether that exposure-related toxicity was related to too much wild-type HTT lowering or the proinflammatory effects of the ASO, you can’t yet disentangle.” Roche has not given up: The company is now seeking to test lower dosages of tominersen on a younger subgroup of patients who have fewer CAG repeats, in whom a benefit of protein lowering might be more clearly seen.
Small molecules and gene therapies have also been developed to reduce mutant HTT, although most, as is the case with tominersen, will also reduce healthy protein.
“There is a long and complex debate about how much [lowering] is too much and how much is enough,” Dr. Sampaio said. “And this is a problem that has not been solved.”
Allele-specific therapy. A different class of investigative drugs, called allele-specific therapies, target only mutant HTT, sparing healthy protein. The drugs are tailored to genetic markers, or single-nucleotide polymorphisms (SNPs), that are present in different Huntington’s disease populations worldwide. Because treatments based on SNPs are highly tailored, “you need a new drug for each SNP to cover the global Huntington’s disease population,” Dr. Sampaio said. “This presents challenges from a regulatory perspective, as each drug would have to be evaluated separately.”
Two SNP-based therapies failed clinical trials in 2021, when they did not engage their targets.2 A third trial succeeded in lowering mutant HTT while preserving healthy protein and is being evaluated further in the clinic.2
Other strategies have yielded disappointing or mixed results:
A trial of branaplam, a small molecule, was stopped late in 2022 after patients developed peripheral neuropathy.3 Novartis, the drug’s manufacturer, said it would no longer investigate branaplam for Huntington’s disease.
Months earlier, in August 2022, a trial of a gene therapy to lower HTT protein – injected directly into the striatum of the brain – was halted because of adverse events in its high-dosage arm but has since resumed, with some changes to protocol.4
In neither case was excess protein-lowering thought to be the cause of safety problems.
DNA repair emerges as a promising target
Scientists have understood, since the 1990s, that the number of excess CAG repeats measured in a blood test is not the sole predictor of the onset of motor symptoms or rate of progression of Huntington’s disease.
Since the early 2000s, researchers have also known that the number of CAG repeats in cells is unstable, both in different tissues and cell types, and over time. People with Huntington’s disease turned out to be genetic mosaics, with varying, changing lengths of CAG repeats in cells. Repeats increase as a person ages, most drastically in the spiny medium neurons of the brain.
The process by which CAG repetitions grow in cells, known as somatic instability, remained poorly understood and little investigated until 2015, when a genomewide association study revealed previously unknown mechanisms.5 As it turns out, genes involved in the growth of CAG repeats are related to the DNA mismatch repair pathway, which is also important in cancer.
DNA mismatch repair refers to a complex housekeeping system, involving multiple genes and enzymes, that is fundamental to the functioning of the body as genes are continuously being translated to form proteins. Mismatch repair becomes increasingly error-prone with age: Mistakes that are not repaired become mutations, some of which are irrelevant and others that can be deleterious and lead to cancer.
In Huntington’s disease, enzymes involved in repairing DNA are the same ones that can erroneously add CAG repeats to HTT. A person with Huntington’s disease inherits what can be considered a “dyslexic” DNA repair system, Dr. Sampaio said, that misreads its template and keeps adding CAGs.
After the 2015 genomewide association study, “the DNA mismatch repair pathway became hugely important in Huntington’s disease research, and there is a lot of attention being paid now to its components. The idea is that, if we can intervene in this process, we might stop the somatic instability, the growing of the CAG repetitions, and ameliorate the progression of the disease,” Dr. Sampaio said.
In 2017 Dr. Tabrizi’s team reported that the mismatch repair gene MSH-3 was as a key driver of CAG repeats in people with Huntington’s disease.6 “I’m working really closely now with DNA repair scientists who’ve been working in cancer for 20 years. Cancer and repeat expansion diseases have really come together,” Dr. Tabrizi said.
At CHDI’s April 2023 therapeutics conference in Dubrovnik, Croatia, scientists presented findings on how to target MSH-3 and other mechanisms that underlie somatic instability.7 (Several drug companies are working on small molecules, ASOs, and other ways to inhibit MSH-3.) Researchers also presented extensively on protein lowering. The two treatment strategies are compatible for Huntington’s disease, Dr. Tabrizi said.
“I think the best way to approach Huntington’s is to target the somatic CAG repeat expansion by inhibiting MSH-3 in some way, and also target HTT lowering – but targeting it at the DNA level, as opposed to clearing the protein,” Dr. Tabrizi said. DNA-centered approaches in preclinical testing include CRISPR gene editing to inactivate mutant HTT and zinc finger proteins that allow selective targeting of DNA to reduce mutant HTT.
Recent findings on the mismatch repair pathway in Huntington’s disease have direct implications for other rare neurologic diseases caused by triplet repeat mutations, including myotonic dystrophy and cerebellar ataxias.
“There is very strong basic fundamental research in Huntington’s disease that doesn’t exist for every disease,” Dr. Sampaio said. “The fact that it is monogenic, and an adult disease that progresses relatively slowly, has made it a good disease to study, a kind of model.”
Huntington’s disease research has also generated research strategies of value in neurodegenerative diseases, such as Alzheimer’s and Parkinson’s. It provided key insights about neurofilament light, a biomarker of neuronal damage, and about the ASO drug class, which is being investigated for its utility treating in a range of diseases.
Previously, Huntington’s disease trial cohorts and registries focused on patients with late symptomatic disease. However, researchers are now pivoting to patients with less-severe disease and to preclinical mutation carriers. “We now know you have to treat early,” Dr. Tabrizi said. “This has implications for the whole field.”
Dr. Sampaio disclosed that she is an employee of CHDI Management, the administrative arm of the CHDI foundation. Dr. Tabrizi disclosed serving as a consultant to Alnylam Pharmaceuticals, Annexon, Ascidian Therapeutics, Arrowhead Pharmaceuticals, Atalanta Therapeutics, Design Therapeutics, F. Hoffmann-La Roche, HCD Economics, IQVIA, Iris Medicine, Latus Bio, LifeEdit, Novartis, Pfizer, Prilenia Therapeutics, PTC Therapeutics, Rgenta Therapeutics, Takeda Pharmaceuticals, uniQure, and Vertex Pharmaceuticals.
References
1. Genentech. Genentech Provides Update on Tominersen Program in Manifest Huntington’s Disease. https://www.gene.com/media/press-releases/14902/2021-03-22/genentech-provides-update-on-tominersen-.
2. Wave Life Sciences. Defining a new era of oligonucleotides. https://ir.wavelifesciences.com/news-releases/news-release-details/wave-life-sciences-announces-positive-update-phase-1b2a-select.
3. Novartis. Community update: Status of VIBRANT-HD, the study of branaplam/LMI070 in Huntington’s disease. https://hdsa.org/wp-content/uploads/2022/08/Novartis-FINAL-Community-Letter-8-24-22.pdf.
4. UniQure. Second Quarter 2022 Financial Results. https://uniqure.gcs-web.com/node/10856/pdf.
5. Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium. Cell. 2015 Jul 30;162(3):516-26. doi: 10.1016/j.cell.2015.07.003.
6. Moss DJH et al. Lancet Neurol. 2017 Sep;16(9):701-11. doi: 10.1016/S1474-4422(17)30161-8.
7. CHDI Foundation. Postcard from Dubrovnik 2023. https://chdifoundation.org/postcard-from-dubrovnik-2023/.
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All rights reserved. This material may not be published, broadcast, copied, or otherwise reproduced or distributed without the prior written permission of Frontline Medical Communications Inc.</copyrightNotice> </rightsInfo> </provider> <abstract/> <metaDescription>BY JENNIE SMITHThe past decade has been a contradictory one for research on Huntington’s disease, marked by breakthroughs in the biology and genetics of this fa</metaDescription> <articlePDF/> <teaserImage>297680</teaserImage> <title>A new chapter for research on treating Huntington’s disease</title> <deck/> <disclaimer/> <AuthorList/> <articleURL/> <doi/> <pubMedID/> <publishXMLStatus/> <publishXMLVersion>1</publishXMLVersion> <useEISSN>0</useEISSN> <urgency/> <pubPubdateYear/> <pubPubdateMonth/> <pubPubdateDay/> <pubVolume/> <pubNumber/> <wireChannels/> <primaryCMSID/> <CMSIDs/> <keywords/> <seeAlsos/> <publications_g> <publicationData> <publicationCode>nr</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> <journalTitle>Neurology Reviews</journalTitle> <journalFullTitle>Neurology Reviews</journalFullTitle> <copyrightStatement>2018 Frontline Medical Communications Inc.,</copyrightStatement> </publicationData> </publications_g> <publications> <term canonical="true">22</term> </publications> <sections> <term canonical="true">75329</term> </sections> <topics> <term>249</term> <term canonical="true">285</term> </topics> <links> <link> <itemClass qcode="ninat:picture"/> <altRep contenttype="image/jpeg">images/24012234.jpg</altRep> <description role="drol:caption">Dr. Cristina Sampaio</description> <description role="drol:credit"/> </link> <link> <itemClass qcode="ninat:picture"/> <altRep contenttype="image/jpeg">images/24012233.jpg</altRep> <description role="drol:caption">Dr. Sarah Tabrizi</description> <description role="drol:credit"/> </link> </links> </header> <itemSet> <newsItem> <itemMeta> <itemRole>Main</itemRole> <itemClass>text</itemClass> <title>A new chapter for research on treating Huntington’s disease</title> <deck/> </itemMeta> <itemContent> <p><br/><br/>BY JENNIE SMITH<br/><br/>The past decade has been a contradictory one for research on Huntington’s disease, marked by breakthroughs in the biology and genetics of this fatal neurodegenerative disease and painful disappointments in trials of novel therapies. <br/><br/></p> <h2>What is Huntington’s disease?</h2> <p>Huntington’s disease is caused by a trinucleotide repeat mutation in the huntingtin gene (HTT) and follows an autosomal dominant pattern of inheritance. In people with more than 39 copies of this CAG repeat tract expansion, the HTT protein misfolds to become toxic, with more repeats linked to earlier disease onset and a more severe course. </p> <p>Huntington’s disease causes loss of neurons in the striatum and disrupts the cortical-striatal-thalamic pathway, a brain circuit that governs movement. Although behavioral symptoms can emerge earlier, signature symptoms – chorea, dystonia, and cognitive abnormalities – usually present at midlife and progress until the patient’s death. <br/><br/>[[{"fid":"297680","view_mode":"medstat_image_flush_right","fields":{"format":"medstat_image_flush_right","field_file_image_alt_text[und][0][value]":"Dr. Cristina Sampaio, chief medical officer of CHDI Management, Princeton, N.J.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][value]":"Dr. Cristina Sampaio"},"type":"media","attributes":{"class":"media-element file-medstat_image_flush_right"}}]]Huntington’s disease affects an estimated 30,000 people in the United States, and an estimated 10-12 people for every 100,000 worldwide – making it rare enough that neurologists who do not specialize in movement disorders might never treat a Huntington’s patient. Yet Huntington’s disease is sufficiently prevalent to attract robust research interest and sustain large registries, which have led to remarkable findings with implications not just for Huntington’s disease but for other diseases as well.<br/><br/>Right now, the only Food and Drug Administration–approved treatments for Huntington’s disease are symptomatic therapies to help temper disturbances of movement, sleep, and emotions. There are two major avenues of investigation into Huntington’s disease modification:<br/><br/><em>Reduce levels of mutant HTT protein</em>, whether through small molecules, gene therapies, or antisense oligonucleotides (ASOs) that modulate RNA processing. In March 2021, Roche announced the suspension of its phase 3 trial of tominersen, an ASO.<sup>1</sup> Trials of other protein-lowering agents were canceled for lack of target engagement or over safety concerns, in 2021 and 2022, although this approach is still considered viable. <br/><br/><em>Modify the length of CAG repeats</em>, which involves a more recently encountered mechanism in Huntington’s disease. The strategy is at the preclinical stage. In 2015, a group of scientists reported the game-changing discovery that a large number of genes, associated with some of the same DNA-mismatch repair pathways implicated in cancer, can modify the length of CAG repeats in cells. This gave rise to a new set of therapeutic targets, now being explored. <br/><br/>Neurology Reviews 2023 Rare Neurological Disease Special Report spoke with two frequently collaborating researchers at the forefront of Huntington’s disease science – Cristina Sampaio, MD, PhD, chief medical officer of CHDI Management, Princeton, N.J., and Sarah Tabrizi, MD, PhD, from University College London – about lessons learned from the past several years of Huntington’s disease drug research. <br/><br/>The CHDI Foundation, a nonprofit research organization, was founded in 2003 to facilitate development of Huntington’s disease therapies. Its clinical research platform, Enroll-HD, includes a global registry of some 28,000 patients and a biobank to facilitate biomarker discovery and validation. Dr. Tabrizi’s lab explores Huntington’s disease drug targets in both HTT and DNA mismatch repair, and led two CHDI-funded observational studies, TRACK-HD and TrackOn-HD, to characterize disease progression in people with Huntington’s disease. In 2022, Dr. Tabrizi and Dr. Sampaio were coauthors of a comprehensive review of Huntington’s disease drug development and published a new disease-staging system to help enable trials in presymptomatic Huntington’s disease. <br/><br/>“The story of Huntington’s therapeutics is very informative,” Dr. Sampaio said. “Understanding these mechanisms is relevant for any neurologist – not only for Huntington’s but because they represent a prototype development for a big group of therapies and make us better equipped to think about everything else that is happening in neurology. They’re giving us an understanding of where neurology is going.”<br/><br/></p> <h2>Tackling a tricky protein</h2> <p>Most Huntington’s disease research has focused on ways to attack or lower mutant HTT protein. But HTT has proven a tricky target: HTT is a large protein, present in all cells, and known to interact with more than 100 genes. Healthy HTT is critical to fetal development, but its functions in the adult body remain something of a mystery. Almost all people with Huntington’s disease have both wild-type and mutant HTT. </p> <p>Tominersen, the investigative ASO developed by Roche, works to block translation of the HTT message, leading to a reduction in both healthy and mutant HTT protein. It is delivered by lumbar injection to reach the brain. Upon halting its phase 3 trial of tominersen in 2021, Roche reported 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. The tominersen program was the first to clearly show that it is possible to lower HTT with an intervention – a critical first step in the development of this class of drugs.<br/><br/>[[{"fid":"297679","view_mode":"medstat_image_flush_right","fields":{"format":"medstat_image_flush_right","field_file_image_alt_text[und][0][value]":"Dr. Sarah Tabrizi, University College London","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][value]":"Dr. Sarah Tabrizi"},"type":"media","attributes":{"class":"media-element file-medstat_image_flush_right"}}]]“I think the problem with the trial was the aggressive loading doses plus exposure-related toxicity,” Dr. Tabrizi said. “Whether that exposure-related toxicity was related to too much wild-type HTT lowering or the proinflammatory effects of the ASO, you can’t yet disentangle.” Roche has not given up: The company is now seeking to test lower dosages of tominersen on a younger subgroup of patients who have fewer CAG repeats, in whom a benefit of protein lowering might be more clearly seen. <br/><br/>Small molecules and gene therapies have also been developed to reduce mutant HTT, although most, as is the case with tominersen, will also reduce healthy protein. <br/><br/>“There is a long and complex debate about how much [lowering] is too much and how much is enough,” Dr. Sampaio said. “And this is a problem that has not been solved.”<br/><br/><strong>Allele-specific therapy. </strong>A different class of investigative drugs, called allele-specific therapies, target only mutant HTT, sparing healthy protein. The drugs are tailored to genetic markers, or single-nucleotide polymorphisms (SNPs), that are present in different Huntington’s disease populations worldwide. Because treatments based on SNPs are highly tailored, “you need a new drug for each SNP to cover the global Huntington’s disease population,” Dr. Sampaio said. “This presents challenges from a regulatory perspective, as each drug would have to be evaluated separately.” <br/><br/>Two SNP-based therapies failed clinical trials in 2021, when they did not engage their targets.<sup>2 </sup>A third trial succeeded in lowering mutant HTT while preserving healthy protein and is being evaluated further in the clinic.<sup>2</sup> <br/><br/>Other strategies have yielded disappointing or mixed results:<br/><br/>A trial of branaplam, a small molecule, was stopped late in 2022 after patients developed peripheral neuropathy.<sup>3</sup> Novartis, the drug’s manufacturer, said it would no longer investigate branaplam for Huntington’s disease. <br/><br/>Months earlier, in August 2022, a trial of a gene therapy to lower HTT protein – injected directly into the striatum of the brain – was halted because of adverse events in its high-dosage arm but has since resumed, with some changes to protocol.<sup>4</sup><br/><br/>In neither case was excess protein-lowering thought to be the cause of safety problems.</p> <h2>DNA repair emerges as a promising target</h2> <p>Scientists have understood, since the 1990s, that the number of excess CAG repeats measured in a blood test is not the sole predictor of the onset of motor symptoms or rate of progression of Huntington’s disease.</p> <p>Since the early 2000s, researchers have also known that the number of CAG repeats in cells is unstable, both in different tissues and cell types, and over time. People with Huntington’s disease turned out to be genetic mosaics, with varying, changing lengths of CAG repeats in cells. Repeats increase as a person ages, most drastically in the spiny medium neurons of the brain. <br/><br/>The process by which CAG repetitions grow in cells, known as somatic instability, remained poorly understood and little investigated until 2015, when a genomewide association study revealed previously unknown mechanisms.<sup>5</sup> As it turns out, genes involved in the growth of CAG repeats are related to the DNA mismatch repair pathway, which is also important in cancer. <br/><br/>DNA mismatch repair refers to a complex housekeeping system, involving multiple genes and enzymes, that is fundamental to the functioning of the body as genes are continuously being translated to form proteins. Mismatch repair becomes increasingly error-prone with age: Mistakes that are not repaired become mutations, some of which are irrelevant and others that can be deleterious and lead to cancer.<br/><br/>In Huntington’s disease, enzymes involved in repairing DNA are the same ones that can erroneously add CAG repeats to HTT. A person with Huntington’s disease inherits what can be considered a “dyslexic” DNA repair system, Dr. Sampaio said, that misreads its template and keeps adding CAGs. <br/><br/>After the 2015 genomewide association study, “the DNA mismatch repair pathway became hugely important in Huntington’s disease research, and there is a lot of attention being paid now to its components. The idea is that, if we can intervene in this process, we might stop the somatic instability, the growing of the CAG repetitions, and ameliorate the progression of the disease,” Dr. Sampaio said. <br/><br/>In 2017 Dr. Tabrizi’s team reported that the mismatch repair gene MSH-3 was as a key driver of CAG repeats in people with Huntington’s disease.<sup>6 </sup>“I’m working really closely now with DNA repair scientists who’ve been working in cancer for 20 years. Cancer and repeat expansion diseases have really come together,” Dr. Tabrizi said. <br/><br/>At CHDI’s April 2023 therapeutics conference in Dubrovnik, Croatia, scientists presented findings on how to target MSH-3 and other mechanisms that underlie somatic instability.<sup>7</sup> (Several drug companies are working on small molecules, ASOs, and other ways to inhibit MSH-3.) Researchers also presented extensively on protein lowering. The two treatment strategies are compatible for Huntington’s disease, Dr. Tabrizi said. <br/><br/>“I think the best way to approach Huntington’s is to target the somatic CAG repeat expansion by inhibiting MSH-3 in some way, and also target HTT lowering – but targeting it at the DNA level, as opposed to clearing the protein,” Dr. Tabrizi said. DNA-centered approaches in preclinical testing include CRISPR gene editing to inactivate mutant HTT and zinc finger proteins that allow selective targeting of DNA to reduce mutant HTT. <br/><br/>Recent findings on the mismatch repair pathway in Huntington’s disease have direct implications for other rare neurologic diseases caused by triplet repeat mutations, including myotonic dystrophy and cerebellar ataxias. <br/><br/>“There is very strong basic fundamental research in Huntington’s disease that doesn’t exist for every disease,” Dr. Sampaio said. “The fact that it is monogenic, and an adult disease that progresses relatively slowly, has made it a good disease to study, a kind of model.” <br/><br/>Huntington’s disease research has also generated research strategies of value in neurodegenerative diseases, such as Alzheimer’s and Parkinson’s. It provided key insights about neurofilament light, a biomarker of neuronal damage, and about the ASO drug class, which is being investigated for its utility treating in a range of diseases. <br/><br/>Previously, Huntington’s disease trial cohorts and registries focused on patients with late symptomatic disease. However, researchers are now pivoting to patients with less-severe disease and to preclinical mutation carriers. “We now know you have to treat early,” Dr. Tabrizi said. “This has implications for the whole field.” <br/><br/>Dr. Sampaio disclosed that she is an employee of CHDI Management, the administrative arm of the CHDI foundation. Dr. Tabrizi disclosed serving as a consultant to Alnylam Pharmaceuticals, Annexon, Ascidian Therapeutics, Arrowhead Pharmaceuticals, Atalanta Therapeutics, Design Therapeutics, F. Hoffmann-La Roche, HCD Economics, IQVIA, Iris Medicine, Latus Bio, LifeEdit, Novartis, Pfizer, Prilenia Therapeutics, PTC Therapeutics, Rgenta Therapeutics, Takeda Pharmaceuticals, uniQure, and Vertex Pharmaceuticals.<br/><br/></p> <h2>References</h2> <p> 1. Genentech. Genentech Provides Update on Tominersen Program in Manifest Huntington’s Disease. <a href="https://www.gene.com/media/press-releases/14902/2021-03-22/genentech-provides-update-on-tominersen-">https://www.gene.com/media/press-releases/14902/2021-03-22/genentech-provides-update-on-tominersen-</a>.<br/><br/> 2. Wave Life Sciences. Defining a new era of oligonucleotides. <a href="https://ir.wavelifesciences.com/news-releases/news-release-details/wave-life-sciences-announces-positive-update-phase-1b2a-select">https://ir.wavelifesciences.com/news-releases/news-release-details/wave-life-sciences-announces-positive-update-phase-1b2a-select</a>.<br/><br/> 3. Novartis. Community update: Status of VIBRANT-HD, the study of branaplam/LMI070 in Huntington’s disease. <a href="https://hdsa.org/wp-content/uploads/2022/08/Novartis-FINAL-Community-Letter-8-24-22.pdf">https://hdsa.org/wp-content/uploads/2022/08/Novartis-FINAL-Community-Letter-8-24-22.pdf</a>.<br/><br/> 4. UniQure. Second Quarter 2022 Financial Results. <a href="https://uniqure.gcs-web.com/node/10856/pdf">https://uniqure.gcs-web.com/node/10856/pdf</a>.<br/><br/> 5. Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium. Cell. 2015 Jul 30;162(3):516-26. <a href="https://www.cell.com/cell/fulltext/S0092-8674(15)00840-5?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867415008405%3Fshowall%3Dtrue">doi: 10.1016/j.cell.2015.07.003</a>.<br/><br/> 6. Moss DJH et al. Lancet Neurol. 2017 Sep;16(9):701-11. <a href="https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(17)30161-8/fulltext">doi: 10.1016/S1474-4422(17)30161-8</a>.<br/><br/> 7. CHDI Foundation. Postcard from Dubrovnik 2023. <a href="https://chdifoundation.org/postcard-from-dubrovnik-2023/">https://chdifoundation.org/postcard-from-dubrovnik-2023/</a>.</p> </itemContent> </newsItem> <newsItem> <itemMeta> <itemRole>teaser</itemRole> <itemClass>text</itemClass> <title/> <deck/> </itemMeta> <itemContent> <p>Setbacks in trials of protein-lowering therapies – mostly over their safety – mask a story of rapid advances and a more recently discovered treatment pathway that also offers promise for other diseases.</p> </itemContent> </newsItem> </itemSet></root>
