Huntington’s disease is a rare, serious inherited neurological disorder that causes progressive degradation or degeneration of nerve cells in the basal ganglia, located at the base of the brain. Affected people are born with a genetic mutation located on chromosome 4, but their symptoms usually do not appear until after the age of 30 or 40 and they can evolve in very different ways, even among relatives. They include changes in movement, thought and behavior that become very disabling. Although there are treatments that help control some of them, there is no cure that slows down or stops the disease.
In search of this therapy, a team led by José Javier Lucas, a researcher at the Higher Council for Scientific Research (CSIC) and the Center for Network Biomedical Research on Neurodegenerative Diseases (CIBERNED) at the Severo Ochoa Molecular Biology Center (CBMSO) , dependent on the CSIC and the Autonomous University of Madrid (UAM), in Spain, has identified a therapeutic target that could guide new treatments.
Although the underlying mutation that causes Huntington’s disease is already known and gene-silencing therapies that prevent its development are being tested, the molecular mechanisms involved still need to be further explored, so that specific targets can be identified towards which to direct treatments. . “There are no curative treatments for most neurodegenerative diseases. Although some are being developed based on gene therapy or antibodies, these have, in addition to their high cost, the disadvantage that they are based on molecules whose large size makes it difficult to access the affected brain areas. That is why it is important to identify new therapeutic targets that can be approached with drugs that are easy to administer”, highlights Lucas.
Their research, which was published in the journal Science Translational Medicine, suggests a new molecular mechanism causing Huntington’s disease that would cause levels of thiamine or vitamin B1, essential in various chemical reactions in the body, to not reach the brain properly, thereby that could be playing an important role in the disease.
Researcher José Javier Lucas working in his laboratory at the Molecular Biology Center. (Photo: Álvaro Muñoz Guzmán)
Vitamins as possible treatment
Specifically, the researchers point out that a process involved in the correct production of certain proteins inside cells, called messenger RNA (mRNA) polyadenylation, undergoes changes in neurodegenerative diseases, which directly links this mechanism to these pathologies. These are cytoplasmic polyadenylation element-binding proteins (CPEBs), which regulate the expression of some genes. As Lucas observes, “one of the genes most affected by the alteration of CPEBs is SLC19A3, which contains the information to generate a protein that is the thiamine transporter”, which reduces the levels of this vitamin in the brain of sick people.
“Thiamine is essential for brain function and, when it is lacking, neurological conditions such as Wernicke-Korsakoff syndrome or Basal Ganglia Disease that responds to Thiamine and Biotin (BTBGD) develop, which it affects the same brain structure as Huntington’s disease: the striatum”, details Sara Picó, researcher at the CBMSO and first signatory of this research, which has shaped her doctoral thesis.
Thus, Lucas’s team has studied this process in Huntington’s disease, the most prevalent of hereditary neurodegenerative diseases and which only affects around 4,000 people in Spain, and has shown that these alterations reduce thiamine levels in the fluid spinal cord of patients, as occurs in individuals with BTBGD. For this reason, the research suggests a new therapeutic possibility.
Alberto Parras, a researcher at the CBMSO and another of the authors of the study, stresses: “As patients with BTBGD recover with the administration of high doses of two vitamins, thiamine to compensate for its reduced transport, and biotin, which increases the expression of the transporter of thiamine, we have tested the treatment in animal models of Huntington’s disease and we have observed improvements in several aspects”.
A ghost for the family
This disease receives its name in recognition of George Huntington, an American doctor who described it in 1872 and who identified its hereditary nature. Although its symptoms can appear at any time, they usually do so in adulthood. They involve psychiatric and motor disorders that evolve slowly over years or decades. Serious mental disorders usually precede motor disorders and include depression, concentration difficulties and finally dementia.
Characteristically, this pathology presents exaggerated movements of the extremities, called choreic movements —which gave rise to its original name as Huntington’s chorea— and uncontrollable facial grimacing. In advanced stages, it makes it difficult to speak, think and impair memory. It can also involve perpetuating complex and painful body positions for hours. All this also leads to frequent suicidal ideas, which has a significant impact on family members and caregivers.
The father of Ruth Blanco, president of the Spanish Korean Huntington Association (ACHE), died of this disease, which other relatives also have. “It affects the person who receives the diagnosis and all family members. Not only because of the symptoms of the disease, but also because it is hereditary and there is a risk that oneself may be a carrier of a neurodegenerative disease, if one has an affected father or mother, ”she emphasizes. “We call it the phantom of Huntington’s disease: when a family member is diagnosed, you live with that phantom until the person at risk either develops symptoms or takes the step to have predictive genetic testing.”
Indeed, after reaching the age of majority, any asymptomatic individual with affected relatives can have a genetic test that determines without a doubt if they present this mutation that invariably predicts the appearance of symptoms at some later point in life. “It is a very delicate matter because, would you like to know your future if you are really going to suffer from a disease for which there is no cure?” asks Blanco.
As Blanco explains, until a few years ago there was only symptomatic pharmacological treatment for involuntary movements, behavioral disorders or sleep problems “which often falls short” because the symptoms are severe and difficult to control or their effects secondary compromise the well-being of the patient. But recently affected people are aware that it must always be accompanied by non-pharmacological treatment, such as speech therapy, occupational therapy or physiotherapy, essential to improve quality of life.
“It is essential that we understand that the research is focused on pre-symptomatic people, who are known to be carriers but who still do not have a disabling neurological failure,” emphasizes Blanco, who highlights two pressing needs for research. On the one hand, “it is very important that these people are in contact with the associations because it would be very sad if there was a clinical trial in the future and we did not have volunteers to recruit.” From the European Huntington’s Association they are launching the Moving Forward project, “focused on giving support to those people, who have special needs, and making it easier for research not to stop.” On the other, it highlights the importance of donating brain tissue from deceased patients. “Thanks to the generous donation of families who have lost Huntington’s disease patients, there are many lines of research open.”
The difficulties in finding patients are known to the team led by Lucas, who is designing a clinical trial, financed by CIBERNED and coordinated by Pablo Mir, from the Seville Institute of Biomedicine (IBIS-CSIC-US-Junta de Andalucía), to analyze whether the high doses of thiamine and biotin required for the therapeutic effect already observed in mice are safe and tolerable by patients with Huntington’s disease. Lucas hopes to start the trial with a small number of patients next January, although he explains that later phases with more individuals will be necessary to evaluate its possible therapeutic efficacy. (Source: Aser García Rada / CSIC)