Tackling a tricky protein
Most Huntington’s disease research has focused on ways to attack or lower mutant HTT protein. But HTT has proven a tricky target: HTT is a large protein, present in all cells, and known to interact with more than 100 genes. Healthy HTT is critical to fetal development, but its functions in the adult body remain something of a mystery. Almost all people with Huntington’s disease have both wild-type and mutant HTT.
Tominersen, the investigative ASO developed by Roche, works to block translation of the HTT message, leading to a reduction in both healthy and mutant HTT protein. It is delivered by lumbar injection to reach the brain. Upon halting its phase 3 trial of tominersen in 2021, Roche reported that people in the high-dosage treatment group did measurably worse – although it remains unclear whether this was caused by excess protein lowering or an off-target effect. The tominersen program was the first to clearly show that it is possible to lower HTT with an intervention – a critical first step in the development of this class of drugs.
Dr. Sarah Tabrizi
“I think the problem with the trial was the aggressive loading doses plus exposure-related toxicity,” Dr. Tabrizi said. “Whether that exposure-related toxicity was related to too much wild-type HTT lowering or the proinflammatory effects of the ASO, you can’t yet disentangle.” Roche has not given up: The company is now seeking to test lower dosages of tominersen on a younger subgroup of patients who have fewer CAG repeats, in whom a benefit of protein lowering might be more clearly seen.
Small molecules and gene therapies have also been developed to reduce mutant HTT, although most, as is the case with tominersen, will also reduce healthy protein.
“There is a long and complex debate about how much [lowering] is too much and how much is enough,” Dr. Sampaio said. “And this is a problem that has not been solved.”
Allele-specific therapy. A different class of investigative drugs, called allele-specific therapies, target only mutant HTT, sparing healthy protein. The drugs are tailored to genetic markers, or single-nucleotide polymorphisms (SNPs), that are present in different Huntington’s disease populations worldwide. Because treatments based on SNPs are highly tailored, “you need a new drug for each SNP to cover the global Huntington’s disease population,” Dr. Sampaio said. “This presents challenges from a regulatory perspective, as each drug would have to be evaluated separately.”
Two SNP-based therapies failed clinical trials in 2021, when they did not engage their targets.2 A third trial succeeded in lowering mutant HTT while preserving healthy protein and is being evaluated further in the clinic.2
Other strategies have yielded disappointing or mixed results:
A trial of branaplam, a small molecule, was stopped late in 2022 after patients developed peripheral neuropathy.3 Novartis, the drug’s manufacturer, said it would no longer investigate branaplam for Huntington’s disease.
Months earlier, in August 2022, a trial of a gene therapy to lower HTT protein – injected directly into the striatum of the brain – was halted because of adverse events in its high-dosage arm but has since resumed, with some changes to protocol.4
In neither case was excess protein-lowering thought to be the cause of safety problems.