Early-stage human trials have shown that a potential treatment for Huntington’s disease — devised by University College London — is both safe and potentially effective. But is it a “breakthrough that may stop the disease” that media reports claim? Huntington’s disease, as of yet, has no cure.
IONIS-HTTRx, a potential cure?
The potential new treatment, IONIS-HTTRx, is unique in that it specifically targets mutant huntingtin, the protein most widely assumed to cause Huntington’s disease. Until now, medications used for the disease have been limited to symptom management and have not addressed the root cause of the disease.
The proposed medication has spent over a decade in preclinical development. In 2015, the medication entered human trials under sponsorship from US-based Ionis Pharmaceuticals. The trials took place across nine study centres in the UK, Canada and Germany and involved 46 participants, each with early stage Huntington’s disease.
An ultra-sensitive assay was used to detect levels of mutant huntingtin in the spinal fluid of the participants both before and after the medication period. The assay found that mutant huntingtin levels were reduced following the medication period, indicating an overwhelmingly positive result.
However, we don’t yet know whether the medicine has actually led to patients having a better outcome. While a cautiously optimistic outlook may be excused given the positive nature of the results, the human trials are only in their initial phases. The study was conducted on a limited sample size of just 46 individuals. Further tests must be conducted to establish whether there are any side effects to the medication or any considerable reductions in disease pathology. As Huntington’s disease is such a complex and poorly understood condition, the medication should not be hailed as a miracle cure in its opening trials.
The cause of Huntington’s disease
Huntington’s disease is a genetic condition. As with many other inherited diseases it has proven difficult to treat. Due to the genetic nature of the disease, a person may harbour the condition all of their life without displaying symptoms. This can allow the disease to be passed from parent to child with no cause to suspect the potential for the disease.
Understanding the genetic cause will be key to treating the disease. Huntington’s disease is an autosomal dominant disorder. This means that only a single parent needs to possess the affected genes to pass Huntington’s disease to their child. The genes involved are characterised by an expansion in the repeated CAG (cytosine, adenine, guanine) triplet, coding for the amino acid glutamine (symbolised as the letter “Q”).
The polyglutamine (polyQ) region — formed of variable numbers of repeated glutamine amino acids — is responsible for the functional and pathological differences between the HTT (Huntingtin) protein and the mutant mHtt protein. The commonly held belief is that the elongated polyglutamine region changes the shape of the huntingtin protein in a way that alters its interactions with other proteins, disturbing its normal function.
The pathology and age of onset of the disease directly correlates to the length of the polyQ region. A person with nine to 35 glutamine repeats is considered to have a normally functioning HTT protein. With a repeat length of 36 to 39 the disease shows incomplete penetrance and symptoms may or may not be apparent. Typically if a person with incomplete penetrance does display symptoms, the age of onset is higher than those with 40 or more glutamine repeats. Due to the late onset coupled with a slow progression of disease pathology, some individuals may only display symptoms very late in life, or may pass away before the disease becomes apparent.
In patients with an excess of 40 glutamine repeats, the disease is fully penetrant. The higher the number of repeats the lower the age of onset. When an individual has children, there is a chance that the polyglutamine repeat lengthens. This can allow for people with incomplete penetrance, or even those with a healthy huntingtin protein, to give birth to a child who is considered to have Huntington’s disease.
In patients with a high number of glutamine repeats, typically above 60, onset of symptoms may occur as early as the age of 20. This is termed “juvenile Huntington’s disease”, with these cases making up around 7% of the total number of Huntington’s disease patients.
Functionality of the Huntingtin protein, still a disputed topic
The Htt protein interacts with over 100 different proteins. Its function and the mechanism by which it induces cell death within the brain — and so produces the symptoms of Huntington’s disease — is currently poorly understood. It is however well documented that Huntington’s disease pathology predominantly affects an area of the brain known as the striatum, as neuron loss is most predominant in this region.
The striatum has been implicated as having a role in the regulation of movement. It is known to be affected in both Huntington’s cases, as well as those with Parkinson’s disease, both disorders in which involuntary movements are common.
Some proposed mechanisms of Huntington’s implicate the protein “Rhes”. This protein is specific to the striatum and has been found to induce sumoylation (a form of protein modification) of the disease-causing mutant huntingtin. This may account for Huntington’s disease pathological predominance within the striatum.
Alternative mechanisms have been proposed involving the effect of mHtt on mitochondria (responsible for energy production within cells), either through a direct interaction or indirectly via mHtt’s effects on gene transcription. This may lead to dysfunctional regulation of metabolism in affected neurons, potentially causing cell death.
Most experts think that the symptoms of the disease are likely derived from the effects of aggregated, cleaved products of mutant huntingtin. Some have suggested the aggregated, non-soluble mutant huntingtin products are capable of interfering with DNA regulation, resulting in cellular dysfunction. It is typically this aspect of the disease that is the focus of research and attempts at treating the disease, though currently there has been no success.
Some have rebutted the claims that aggregation is the cause of the disease. They think that the formation of aggregates is a means by which the cell may protect itself from the effects of the soluble, individual mHtt residues. This would imply that the protein is far more damaging to the cell in its soluble form, potentially due to increased availability to react with other components of the cell.
Mutant huntingtin has also been shown to disrupt axonal transport due to mHtt aggregation. Potentially this may lead to the abnormal build-up of proteins within the neuron. This can signal for apoptosis (destruction of the cell) to occur.
Huntington’s disease symptoms
Huntington’s disease pathology is characterised by a triad of symptoms, involving motor, cognitive and psychiatric dysfunction. Patients are also prone to depression, anxiety and obsessive compulsive disorders more than ten years prior to diagnosis with Huntington’s disease.
Diagnosis of Huntington’s disease typically occurs when motor problems become apparent in the patient. One of the hallmark symptoms of the disease is the loss of motor function, this leads to uncontrolled movements referred to as “chorea”.
Loss of motor function progresses over the course of Huntington’s pathology to the point that rigidity, difficulty walking, facial distortion and difficulty speaking become common. These symptoms have been shown to correlate with striatal atrophy occurring at the early stages of the disease.
Weight loss is as a symptom of the disease through a combination of muscular issues leading to difficulty in both chewing and swallowing. As muscular problems begin to affect day to day life, a patient may find themselves becoming more and more reliant on care from others. For many, this will involve consistently increasing assistance from family members, often amounting to full time care, leaving the patient an economic burden, particularly to poorer families.
Cognitive decline is characteristic of Huntington’s disease. In the early stages of the disease, cognitive processes such as abstract thinking and planning are affected. As the disease symptoms progress, a decline in memory is often observed. Some patients have described the condition as Parkinson’s disease, Alzheimer’s disease and motor neuron disease combined into a single condition.
Psychiatric issues can occur across the course of the disease, with symptoms ranging from paranoia to hallucinations as well as intellectual decline. These symptoms can become so severe that a patient may be institutionalised.
A unique treatment, but no guarantee
“The results of this trial are of ground-breaking importance for Huntington’s disease patients and families. For the first time a drug has lowered the level of the toxic disease-causing protein in the nervous system, and the drug was safe and well-tolerated,” said Professor Tabrizi, Director of the UCL Huntington’s Disease Centre and IONIS-HTTRx Global Chief Investigator.
“The key now,” she adds, “is to move quickly to a larger trial to test whether the drug slows disease progression.”
Indeed, IONIS-HTTRx seems a promising therapy, with positive initial results and a mechanism of action that directly addresses what is considered to be the root cause of Huntington’s disease. Current therapies are limited to symptom management. These are based around the effects the disease has on the individual patient and can include standard antipsychotics, as well as drugs such as tetrabenazine to control muscle spasms.
The IONIS-HTTRx medication marks the first example of a drug aimed towards halting the progression of the disease. As such, it appears a step in the right direction. However, further trials are needed before the treatment’s benefits can be claimed as they have been in the media thus far.