Huntington’s disease (HD) is a genetic neurodegenerative disorder that was first described in 1872 by the physician George Huntington,1 in his seminal paper ‘On Chorea’. Huntington described the condition as a hereditary, progressive, adult-onset disease that caused patients to suffer from a range of cognitive, motor, and behavioural symptoms2,3 (Fig.1). Since that time, HD has been studied extensively, allowing scientists to develop a thorough understanding of the disease´s pathology and symptoms. However, to date, there is no effective therapy available to treat this highly debilitating and ultimately fatal disease.
What causes Huntington’s Disease?
To understand what goes wrong in HD, we must first understand how the deoxyribonucleic acid (DNA) within cells is used to make proteins. Proteins are molecules that are necessary for the normal function of a cell, and the instructions that are required to synthesize them are contained within the genetic information of the cell, the DNA. The DNA in turn is made up of a series of molecules called nucleotides, and the set of nucleotides that codes for a protein is called a gene. The DNA nucleotides are named after one of their components, which is called a nitrogenous base. The four nitrogenous bases that form DNA are adenine (A), cytosine (C), guanine (G), and thiamine (T). However, a gene cannot be directly used to make a protein. An intermediate molecule called messenger RNA (mRNA) must first be formed. This molecule provides the code for the assembly of individual proteins. In HD, the protein, huntingtin, is encoded by the huntingtin (HTT) gene. The HTT gene, which is found on chromosome 44, contains the trinucleotide CAG, made up of nitrogenous bases, cytosine, adenine, and guanine. This trinucleotide, which codes for the amino acid glutamine, is repeated a variable number of times within the DNA sequence of the HTT gene, and it has been discovered that it is the total number of CAG repeats that is present in the HTT gene of an individual, that determines whether or not an individual will develop HD. Individuals with less than 27 repeats do not develop symptoms of HD. Similarly, individuals with 27 – 35 repeats are typically healthy, although in some rare cases they may develop symptoms of HD6. It has been found that the number of CAG repeats present in the HTT gene tends to increase from generation to generation, and therefore while individuals who have 27 – 35 CAG repeats in their HTT gene might not be at risk of developing HD, their children may have a greater number of repeats in their HTT gene and be at risk of developing HD. When the number of repeats exceeds 35, the risk of developing HD increases further. The presence of over 40 CAG repeats in an individual´s HTT gene has been found to correlate with the certain development of disease.
As described earlier, the HTT gene codes for the protein, huntingtin. In individuals with HD, a greater number of CAG repeats (> 35) is present in the HTT gene, which leads to a greater number of glutamine amino acids in the huntingtin protein that is made. This abnormal version of the huntingtin protein tends to form clumps called aggregates, which are toxic to neurons (nerve cells)7. This toxicity leads to neuronal death. The most vulnerable neurons are those that make up the dorsal striatum, a region of the brain that is made up of two brain structures, the caudate nucleus and the putamen (Fig.3). As time passes, more brain areas become affected8. The dorsal striatum is part of a network of brain structures called the basal ganglia (Fig. 3), which play a critical role in the control of movement. Neuronal death in this region leads to the symptoms of HD (Fig.1), with death typically occurring 15-202 years following the initial diagnosis.
Age of onset and diagnosis
The mutated HTT gene is passed on from generation to generation in an autosomal dominant manner. This means that a child with a parent that has HD has a 50% chance of also getting the disease (Fig.4). The majority of HD patients inherit one normal gene and one mutant gene. Although HD was first described as an adult-onset disease, it is now recognised that patients can present with symptoms at any age, with ages ranging from 2 – 8510. In a small percentage of patients (5 – 10%)11, symptoms appear before the age of twenty-one and this condition is called juvenile HD. Conversely, a small percentage of patients (4 – 12%)12 present with symptoms after the age of sixty and this is termed as late-onset HD. However, in the majority of cases, symptoms appear between the ages of 30 – 50 and this is termed adult-onset HD. Although there is a great degree of overlap between all three types of HD, there are differences in how the disease presents, and how it progresses in individuals with different types of HD. For example, adult-onset patients tend to present with hyperkinetic symptoms, such as chorea. Conversely, patients with juvenile HD typically present with hypokinetic symptoms13 such as bradykinesia (slowness of movement). While seizures are a common symptom of juvenile HD12, they are uncommon in patients with adult-onset and late-onset HD. It has also been observed that the disease tends to progress faster in juvenile HD patients11 compared to adult-onset patients, while the opposite is true for the late-onset population.
The diagnosis of HD requires a neurological examination followed by a genetic test that can confirm the existence of the faulty HTT gene5. A genetic test can also be carried out in individuals that do not present with symptoms, but who may suspect they might develop HD in the future, due to a positive family history. This type of testing is called pre-symptomatic testing. Additionally, prenatal testing can be carried out during pregnancy or during pre-implantation, in the case of in vitro fertilization (IVF), to determine whether a fetus is a carrier of a faulty version of the HD gene5. Hence, genetic testing can be used in several different settings and it can help to inform important life decisions.
Gene therapy and Huntington’s Disease
There is currently no cure for HD and currently available treatments do not target the underlying cause of the disease and only treat the symptoms. However, HD is currently the focus of some highly innovative research and clinical trials. Two branches of therapy are being investigated for HD drug development and gene therapy. In gene therapy, the target of the therapy can be either the disease-causing gene itself or the mRNA that is produced from it. New approaches in gene therapy include the use of antisense oligonucleotides or the technique of RNA interference (RNAi).
As described earlier, RNA is a type of molecule in the cell which has a variety of functions. One type of RNA, mRNA, provides the code for making proteins such as huntingtin. However, there are also other types of RNA and some of these are involved in the process of RNAi. An example of a type of RNA molecule that can carry out RNAi is microRNA. In RNA interference, short RNA molecules combine with cellular proteins to create a complex. This RNA-protein complex can interact with specific mRNAs within cells and cause their destruction, thereby reducing the concentration of these particular mRNAs within the cell14. If less of a specific mRNA is present, less of the protein that it encodes is made. In the context of HD, RNAi can be used to lower the levels of huntingtin mRNA and thereby lower the overall levels of huntingtin protein in the cell. The thinking behind this approach is that lowered levels of faulty huntingtin protein in the cell could protect neurons and slow down the progression of the disease. There are two RNAi therapeutics currently undergoing clinical trials for the treatment of HD and these are called AMT-130 and VY-HTT01.
AMT-130 is a gene therapy that was developed by the company UniQure. It is made up of a gene that is enclosed in an adeno-associated viral vector. A viral vector is a virus that cannot cause disease and is being used as a vehicle to deliver therapeutics to cells. Adeno-associated viruses are viruses that are unable to replicate on their own. Hence, they need to co-infect cells alongside other viruses, such as adenoviruses, from which they derive their name. The gene enclosed in the vector codes for a microRNA that can lower the levels of huntingtin mRNA via the RNAi pathway. This therapy is injected directly into the dorsal striatum of patients during a surgical procedure15. AMT-130 is currently undergoing two different clinical trials. The AMT-130 US trial (NCT04120493) is a phase I/II trial in which a total of 26 patients will participate. Six patients will receive a low dose, ten patients will receive a high dose, and ten patients will receive a mock surgery that simulates the process by which AMT-130 is administered16. The enrolment of patients for this trial started in 2019 and patients are still actively being recruited. As of June 2021, a total of seven patients have received the AMT-130 treatment and five have received the mock surgery17. The trial aims to determine whether AMT-130 is safe, how long it persists in the brain and its effect on disease progression. Simultaneously, a smaller-scale phase I/II trial of AMT-130 with a total of 15 participants will also be conducted at multiple centres across Europe. However, this trial has yet to begin recruitment. The other gene therapy for HD employing RNAi is VY-HTT01. This therapy, which has been developed by the company Voyager, shares many similarities with AMT-130. It is also made up of a gene encoding a microRNA that is enclosed in an adeno-associated virus vector18 and it is directly injected into the brain via a surgical procedure. As of August 2021, Voyager Therapeutics has terminated plans to enter VY-HTT01 into clinical trials. Behind this decision lies the development of a new adeno-associated viral vector technology, which the company hopes will produce a safer and more effective treatment. As of now, the re-designed therapy has entered pre-clinical trials.
Personalized medicine for Huntington’s Disease
Each cell contains DNA and this DNA is inherited in the form of chromosomes. Human cells contain 46 chromosomes, with 23 of these chromosomes being inherited from each parent. This means that every cell contains two sets of each chromosome, and hence two versions of every gene. The different versions of a gene are called alleles. In the majority of HD cases, patients inherit one mutated, disease-causing gene and one normal version. This means that these patients produce both the normal and toxic huntingtin proteins. The treatments described previously lowered the levels of both the normal and the toxic protein. However, this might not be the best approach to treatment, as the normal huntingtin protein might play an important role in the nervous system, and it might even be protective against further neurodegeneration in HD20. Hence, more precise treatments are being developed that only target the toxic protein, thus minimizing the side effects of the treatment20. Two different approaches are being taken towards developing more precise treatments. One of these approaches targets the difference in the number of CAG repeats between the normal and the mutated allele20. However, this approach depends on there being a large enough difference in the repeat numbers between the two alleles. The other approach targets single nucleotide polymorphisms (SNPs)20.
As described earlier DNA is made up of nucleotides. SNPs are simply single nucleotide differences between the two alleles (Fig 5). Both of these approaches recognize the unique genetic features of each HD patient and therefore, this is an example of personalized medicine, where differences between patients are targeted to make more precise and effective treatments. One example of a precision gene therapy in HD is WVE-003, which was developed by Wave Life Sciences. WVE-003 belongs to a class of therapeutics that is called antisense oligonucleotides. Antisense oligonucleotides are short strands of DNA that lower the levels of mRNA in the cell by binding to and causing the destruction of target mRNA, similarly to RNA interference therapies21. WVE-003 targets a specific SNP called SNP3 which is present in the HTT gene of an estimated 40% of HD patients. WVE-003 is currently undergoing a phase I/II clinical trial called SELECT-HD, at multiple locations in Europe, Australia, United Kingdom, and Canada. The trial began enrolment in March 2021 and continues to recruit patients.As of September 2021, the first enrolled patients have received the drug, although no data from the trial is available as of yet.
Drug therapies: Current uses
Drug therapies have traditionally been used to relieve the symptoms of HD without slowing down disease progression. This can be achieved in a number of different ways. For example, some drug therapies target particular neurotransmitters, which are molecules that help neurons to communicate with each other. A neurotransmitter that plays a very important role in HD is dopamine. When acting in the basal ganglia, dopamine always promotes movement, and therefore it is a target for the treatment of chorea, a hyperkinetic symptom. There are two major classes of drugs that are used to treat chorea and these are neuroleptics and VMAT-2 inhibitors3, both of which act on dopamine in the brain. Neuroleptics such as quetiapine are dopamine receptor antagonists, which means that they block the effect of dopamine in the brain. Neuroleptics can be used to treat chorea, psychotic symptoms, anxiety, and irritability in HD. On the other hand, VMAT-2 inhibitors such as tetrabenazine and deutetrabenazine act by reducing the release of dopamine from neurons, thereby inhibiting excessive movement. Currently, tetrabenazine is the preferred treatment for chorea3, unless the patient in question has poorly managed depression or is experiencing suicidal thoughts, as it is known that tetrabenazine may exacerbate these problems3. In addition to movement symptoms, HD patients experience psychiatric symptoms, such as depression and anxiety. Both depression and anxiety are treated with antidepressants such as selective serotonin reuptake inhibitors and certain noradrenaline r-uptake inhibitors3. However, anxiety may also be treated with neuroleptics or anxiolytics3. Patients often also experience sleep disturbances such as insomnia. In such cases, hypnotics may be used. However, the use of hypnotics can lead to dependence on these medications. An alternative to hypnotics is treatment with antihistamine drugs or antidepressants3.
Drug therapies: New advances
As our knowledge about HD expands, so does the list of drugs that are being used to treat this highly debilitating disease. One interesting drug that is currently in clinical trials is pridopidine. Pridopidine, similarly to neuroleptics and VMAT-2 inhibitors, also interferes with the action of dopamine. Dopamine, as discussed previously, is a type of molecule called a neurotransmitter that promotes movement. More specifically, dopamine promotes both voluntary and involuntary movements. The motor symptoms of HD patients include the gradual deterioration in the ability to performing voluntary movements such as swallowing and the appearance of involuntary movements such as chorea. Therefore, an ideal treatment for HD would encourage voluntary movements and inhibit involuntary movements.
Pridopidine does two important things. Firstly, it increases the level of dopamine in the brain22, which promotes voluntary movement, and secondly, it blocks the effect of dopamine on involuntary movement22. Pridopidine also interacts with a protein called the S1 receptor protein, which is important for the normal function of the cell. It is thought that by interacting with this receptor, pridopidine protects neurons from death, thereby slowing down the progression of the disease. Pridopidine has been assessed in several clinical trials, including the MermaiHD (NCT00665223), HART (NCT00724048), and PRIDE-HD (NCT02006472) trials, for which results were published in 2011, 2013 and 2019, respectively. Although pridopidine failed to produce a significant improvement in motor symptoms in all three trials, an improvement could be noted with regards to the motor symptoms of HD24,25,26. Additionally, further analysis of the PRIDE-HD trial data showed that pridopidine produced a significant result in a measurement known as total functional capacity (TFC)27. The TFC score describes the ability of patients to carry out tasks by themselves, such as eating, drinking, walking and working. As the disease progresses, TFC declines. Pridopidine slowed down this decline, demonstrating that it can potentially slow down disease progression. Based on this exciting finding, in the year 2020 researchers began a phase III trial called PROOF-HD (NCT04556656), which aims to further investigate the effect of pridopidine on TFC. The study is expected to complete enrolment by the end of October 2021.
The other HD drug that is currently undergoing clinical trials is ANX005. ANX005 is a type of drug known as an antibody. Antibodies are proteins that are vital for our immune response against infections. Antibodies bind to pathogens such as viruses and help to eliminate them. However, antibodies can also be designed and produced for use as drugs to target harmful molecules in our bodies that cause disease. In the case of ANX005, the target is a protein called C1q. The C1q protein is a necessary part of our immune response against pathogens. However, it is thought to contribute to cell death in diseases such as HD28. The thinking behind this approach is that by producing an antibody against it and administering this to HD patients, the levels of C1q in the brain can be lowered, thereby preventing neuronal death and slowing down the progression of the disease. ANX005 is currently being assessed in a phase II clinical trial (NCT04514367), which aims to determine whether ANX005 is safe and well-tolerated by patients. This trial is currently ongoing and is anticipated to conclude in 2022.
Conclusion: Huntington’s disease in the future
Huntington’s disease is a rare neurodegenerative disease in which neuronal cell death is caused by a mutation in the HTT gene, which encodes the huntingtin protein. The mutation results in a large (> 35) number of CAG trinucleotide repeats being present within the DNA sequence of the HTT gene, and the mutated version of the gene is passed on in an autosomal dominant manner (Fig.4). The mutated huntingtin protein causes neuronal cell death, leading to the motor, behavioural, and cognitive symptoms that characterise HD. While HD can develop at any age, the age range of HD patients is typically between 30 – 50 years of age. HD is diagnosed by carrying out both a neurological examination and a genetic test, although pre-symptomatic and prenatal genetic testing is also available for those at risk. Although Huntington’s Disease is currently considered to be an incurable disease, for which only symptomatic relief is possible, it is hoped that this may change soon, due to new and exciting innovations in treatment. Gene therapy is a type of therapy in which either the faulty, disease-causing gene or the mRNA that is produced from it is targeted. By targeting the underlying cause of the disease, gene therapies have the potential to protect neurons from degeneration and slow down the progression of the disease. Currently, RNA interference and antisense oligonucleotides are at the forefront of gene therapy for HD, with therapies such as AMT-130, VY-HTT01 and WVE-003 currently being assessed in clinical trials. All three therapies aim to lower the levels of huntingtin in the neurons of patients, with WVE-003 reducing only the mutant form of the protein in cells. Regarding drug therapy, pridopidine and ANX005 challenge the notion that drugs can only offer symptomatic relief, as both of these drugs have the potential to slow down the progression of the disease. In conclusion, although HD is currently considered to be incurable, it is possible that in the near future, exciting innovations in the fields of gene and drug therapy will lead to an improved quality of life and possibly a cure for HD patients, putting an end to this devastating illness.
What is it like to live with Huntington’s Disease?
Gene therapy for Huntington’s Disease
RNA interference (RNAi)