Advances in Treating Mutant Protein Linked to Huntington’s Disease

According to an article originally published by HDBuzz, a number of exciting advances have been made in the development of treatments that hope to treat thousands of potential Huntington’s disease (HD) patients by decreasing the presence of mutated huntingtin proteins that aren’t found in healthy individuals.

The treatments come from a number of different biotechnology companies and go about targeting the mutant huntingtin proteins (which cause HD) in an equally diverse number of ways. Some technologies have progressed further down the clinical path than others, but have blind spots and may not be suitable for certain people with HD. That’s why developing a multitude of treatments is so important to researchers.

What is Huntington’s Disease?

Huntington’s disease is a highly rare inherited disease affecting about .003% to .007% of people with European ancestry. It occurs in certain other populations too, albeit at a drastically lower prevalence.

Huntington’s causes a slow breakdown of the nerve cells found in the brain. This neurological degeneration can cause a number of problems in an individual, such as the development of spontaneous involuntary movements called chorea, or changes in reasoning or personality.

Patients with adult-onset HD (the most common form of the disease) typically develop symptoms in their 30s and 40s. These individuals have a life expectancy of around 15 to 20 years after observing their first symptoms.

Huntington’s is caused by a mutation in the HTT gene. The HTT gene is found on the fourth chromosome, and is responsible for coding the production of a protein called huntingtin. Huntingtin is found throughout the body in both healthy and diagnosed individuals, though it seems to be most concentrated in the brain. The function of huntingtin is still not completely understood by researchers, though it is thought to be critical in prenatal development and linked to the growth of brain neurons.

A certain segment of the HTT gene is characterized by a long repetition of three nucleotides – cytosine, adenine, and guanine. Those three bases repeat between 10 and 35 times in healthy individuals; but in those with Huntington’s, this three-base sequence can repeat over 40 times. This stretch of genetic information is cleverly referred to by scientists as the CAG trinucleotide repeat. This error in the CAG loop results in the production of a mutant form of huntingtin that is unusually elongated. This form of the protein tends to fragment into smaller pieces that disrupt brain function and lead to degeneration.

Huntingtin Lowering

One of the more promising forms of Huntington’s treatment is appropriately called huntingtin lowering. There are a number of ways to decrease the high concentrations of mutant huntingtin proteins in individuals with HD, and researchers are investigating every one to determine which might be the most suitable for human use.

Technique One: Antisense Oligonucleotides

Antisense oligonucleotides (or ASOs) are heavily modified strands of DNA that are inserted artificially into cells, where they seek out and destroy certain targeted segments of mRNA. mRNA is kind of like a facsimile of an individual’s DNA used to pass on instructions to various parts of the cell. By destroying these mRNA strands, the message to produce faulty huntingtin is intercepted between the permanently mutated HTT gene and various organelles.

Ionis and Roche

Ionis and Roche, together with Genentech, are the closest thing to veterans in huntingtin lowering there is. Their ASO program is currently being tested in Huntington’s patients, and is set to begin phase III trials before long.

The treatment is effective, but none too focused. All forms of the huntingtin protein are lowered in patients undergoing Ionis and Roche’s treatment – not just the HD-causing mutant versions. The results are promising, but scientists are still hopeful for a more targeted solution, especially when considering the poorly understood nature of huntingtin.

Wave Life Sciences

Wave Life Sciences are hoping to develop just that. They’re working on the formulation of a few different ASOs that target specific versions of the malfunctioning HTT gene.

By targeting certain “spelling” differences in the HTT gene (variations in the nucleotide base sequence) that are outside of the classically HD-signaling CAG trinucleotide repeat which would mean only the number of mutated huntingtin proteins would be lowered. The normal huntingtin is left unaffected, providing a minimally “invasive” form of therapy.

However, the drawback to this more specific form of ASO therapy is that it is only effective in those patients who have the corresponding nucleotide spelling differences that the treatment uses to identify targets. HD patients without these associated spelling quirks can’t be treated with Wave Life’s ASO.

Technique Two: Small Molecule Drugs

PTC Therapeutics is involved in the development of “small molecule” treatments. Small molecule treatment uses a highly specialized drug that acts on a microscopic enough level to enter cells and interfere with the harmful segments of mRNA that code for mutant huntingtin.

Development of the technique is still in its early stages, with PTC only just announcing the drug’s success in animal trials. A number of steps in the treatment’s clinical development remain before human testing can proceed, though scientists are hopeful that small molecule drugs might make treatment for Huntington’s much less physically demanding – requiring fewer injections than current pharmacological treatments.

Technique Three: Gene Therapy

Voyager Therapeutics has taken the hot topic of gene therapy and introduced it to Huntington’s treatments.

Gene therapy is a young but fast-growing and popular field of study in disease research. Not unlike ASO treatments, gene therapy relies on lab-altered genetic material being introduced into affected individuals. However, the means by which they’re introduced differ entirely.

Gene therapy involves the modification of a small, otherwise harmless virus. Viruses are exceptionally good at working their way into cells – and these modified viruses are no exception. When introduced to a patient with Huntington’s, the virus will actually reprogram cells to hunt and destroy huntingtin mRNA.

Unlike ASOs, gene therapy has the potential to reach deep parts of the brain that are often affected in those with HD. While ASOs might require a number of regular injections to function, gene therapy could potentially be as easy as one and done.

But that one-and-done nature also makes researchers hesitate. Promising results in animal testing distract from the fact that humans brains are much more complex than those of animals, even those that are most similar to our own. Some scientists are concerned about the still uncertain potential side effects of the treatment, especially when considering that “treatment” is permanent.

The convenience of gene therapy is also effectively its curse.

Covering Each Others’ Blind Spots

All of these potential treatments have their drawbacks. They may target both mutant and non-mutant huntingtin indiscriminately, or might require significant additional testing to determine if they’re safe in humans at any level.

In fact, the sheer magnitude of difficulties facing down these manufacturers and their inventions might seem discouraging. There’s no guarantee that any of the above treatments will prove effective even in trials, let alone gain FDA approval.

That said, when examined as a collaborative effort undertaken as a broader scientific community rather than a race between competing drug retailers, the report takes on a brighter light. Huntington’s disease is no simple nut to crack, and no one treatment will ever be enough. To provide effective treatment for HD patients in the future, we will need all the viable options we can find.

In what ways can competition between biotechnology companies benefit rare disease patients? In what ways can it hurt? Share your thoughts with Patient Worthy!

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