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Discovery
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Carina Peritore

Recent Setbacks in Huntington’s Disease Therapy

Like the familiar struggles in Alzheimer’s drug development, trying to find Huntington's drugs that stick remains a long game

Two years ago, Biogen halted its clinical trials for Alzheimer’s disease (AD) due to the futility and safety concerns of their BACE inhibitors. Some but not all large pharmaceutical companies de-invested and terminated late-stage development of similar drugs, and in the last five years, researchers have continued to diversify their research away from the amyloid plaque thesis that dominated the field for decades.

Researchers are now looking at treatments that target neuroinflammatory strategies, microglia-modulating drugs, and vascular factors among others. Researchers are also studying an increasing number of drugs that have won prior government approval for non-Alzheimer’s disease (AD) treatments. These repurposed drugs now account for ~30% of the drugs being tested for Alzheimer’s, including  Metformin, Losartan and Candesartan prescribed for type 2 Diabetes and  other cardiac and metabolic disorders.

The diabetes drug is a particularly interesting development because we know this metabolic condition is reversible. Could it be that brain disease is also reversible? This is in line with recent thinking, which views AD as a complex multifactorial disorder. Rather than dominated by one dominant biological factor, such as amyloid-β, AD is likely a confluence of many pathobiological mechanisms, including vascular dysregulation. In fact, there is now a lot of research suggesting this connection between AD and our vasculature, although the puzzle is far from solved. What we do know is that when blood vessels, hence our vasculature are damaged from conditions like type 2 diabetes they represent a huge risk factor for AD.

Progress and Challenges on the HD Front

Which brings us to another neurodegenerative disorder—Huntington’s disease (HD). Unlike the mounting research suggesting lifestyle changes can prevent non-familial, sporadic AD, HD is a rare, fatal neurodegenerative disorder caused by a mutation in a single gene—CAG trinucleotide repeat expansions in the HTT gene.

Everyone has this CAG gene, one inherited from each parent. HD is autosomal dominant meaning that a defect in only one of the two copies of a gene is sufficient to cause the disease. Healthy people normally have the CAG trinucleotide repeated 10 to 35 times in their HTT genes. In people with HD, it may be repeated 36 to more than 120 times. The longer the repeat region, the earlier the onset. It is not 100% penetrant in that people with 26-39 repeats may or may not develop HD during their lifetime, while people with 40 or more repeats almost always develop the disorder.

In this sense, it is known what causes HD whereas outside of a few rare risk genes in AD, you do not have to have a family member who has had it to develop it. Most drugs so far for HD are being developed to treat the downstream effects of the disease. Unfortunately, these drugs come too late in the patient’s life to halt or reverse progression of the disease. With diseases like HD, drugs can be developed with a specific target, the trinucleotide gene that creates an overabundance of the Htt protein vs. the downstream effects of the protein, though there are none available yet for patients.

Although, alternative routes and downstream effects are in fact being investigated for the treatment of HD. For example, researchers at CHDI and Charles River have been investigating ATM (ataxia-telangiectasia mutated) protein, a kinase involved in the DNA damage response, apoptosis and cellular homeostasis for age-related neurodegeneration. ATM signaling was consistently elevated in cells derived from HD mice and in brain tissue from HD mice and patients. ATM knockdown has been shown to protect from toxicities induced by mutant HTT (mHTT) so researchers have been developing small molecule inhibitors of this protein in hopes it can achieve the same results in humans. Another route of therapeutic intervention for HD is the small molecule inhibition of histone deacetylase (HDAC) isoforms which were previously found to contribute to disease progression. Small molecule HDAC inhibitors have been shown to knock down and reduce accumulation of misfolded Htt protein and this route of therapeutic intervention improved HD phenotypes in mice.

The growing footprint of ASOs and gene therapies

More recently, the pharmaceutical industry has shifted its focus to using a gene as a therapeutic intervention. Again, there have been challenges. While there was some initial optimism around a small molecule therapeutic known as an antisense oligonucleotides (ASO), Roche in Switzerland and Wave Life Sciences in Cambridge, MA, halted their Phase III and Phase I/II trials respectively because the therapies were unsuccessful.

ASOs are considered an RNA-based therapy where researchers engineer oligonucleotides that are complementary to specific mRNA sequences. The ASOs are taken up into the cells which degrade the mRNA encoding a specific protein. Roche’s tominersen showed promising results in a Phase I/II trial; it lowered mutant huntingtin in cerebrospinal fluid (CSF) without serious side effects. However, it was halted because the risks were too great. Following a period of review, experts concluded that the drug performed worse than placebo on several outcome measures.

Some have suggested that because the drug suppresses production of both healthy and mutant forms of huntingtin, suppressing the normal protein could have deleterious effects. This is where understanding the true function of the normal protein could be advantageous, and researchers are still trying to understand what huntingtin does. What we do know is that it is expressed in many of our body’s cells with the highest activity in the brain.

Others suggest that the ASO did not reach the right part of the brain to have any sort of beneficial effect. Oligonucleotide delivery is not trivial and remains an ongoing area of development. It is also possible, like the AD drug failures, that the disease was simply too far along to have any beneficial effect in the patient cohort.

Gene therapy and genetic therapies like ASO may well revolutionize the treatment of neurological disorders in the coming decades. Certainly, the recent approval of the gene therapy drug for spinal muscular dystrophy (SMA) is reason to cheer.  However, there are still great challenges as the HD clinical trials have proven. Hopes for an ASO treatment for HD may have been thwarted for the time-being. HD researchers are awaiting the results and outcomes of a large Phase III trial of an ASO for the motor neuron disease amyotrophic lateral sclerosis, or ALS, as they continue to reflect on ASOs for HD.  The pharmaceutical company uniQure is in Phase 1/2 trials of its gene therapy, utilizing an AAV to deliver microRNA to silence the Huntington gene, with the first 10 HD patients now dosed. Meanwhile, Novartis just announced that it will commence Phase 2 studies in HD with branaplam, a small molecule huntingtin-lowering strategy.

One step forward, one step back and one on hold it seems.