Early Study Finds Huntingtin-lowering Compounds That Show Therapeutic Potential

Researchers have developed a new class of compounds that tackles the root cause of Huntington’s disease, opening up new avenues for the development of novel therapies for the disease.

The compounds can lower the levels of mutant huntingtin — the faulty protein in Huntington’s disease — by sending it to special compartments within cells that break it down, without affecting the normal form of the protein.

The research was published in a study, “Allele-selective lowering of mutant HTT protein by HTT–LC3 linker compounds,” in the journal Nature.

Huntington’s disease is caused by a mutation in the huntingtin (HTT) gene, which leads to defects in huntingtin (HTT) protein. These defects trigger the degeneration of certain areas in the brain, namely the basal ganglia and cortex, two regions that play key roles in movement and behavior control.

Mutations in the HTT gene result in the production of a longer-than-normal huntingtin protein that contains an expanded array of glutamine units (polyglutamine, polyQ). Glutamine is a type of amino acid, the building blocks of proteins.

This mutant huntingtin (mHTT) is cut into smaller pieces that stick together and accumulate inside nerve cells (neurons) in the brain, disrupting their normal function and eventually causing their death. The result is the onset and progressive worsening of Huntington’s symptoms.

The disease is autosomal dominant, which means that a person needs to inherit one copy of the defective gene from a parent to develop the disease, even if they carry a normal copy of HTT. People inherit two copies of genes, one from their father and one from their mother. So a child of an affected parent has a 50% chance of developing the disease.

No treatment to halt, slow, or reverse the progression of Huntington’s is currently available. Conventional treatment discovery is challenging because scientists do not know exactly which part of mHTT activity should be blocked to prevent its toxicity.

But a new idea born among researchers from Fudan University, in China, may offer hope for a future therapy.

The innovative approach consists of destroying mHTT protein within cells by harnessing a cell’s recycling pathway called autophagy.

During autophagy, a protein called LC3 is key to engulfing damaged or unwanted proteins, fats, and cell structures for destruction. LC3 traps these molecules within vesicles called autophagosomes, which merge with other vesicles called lysosomes. Lysosomes contain a wide variety of enzymes that break down these engulfed substances.

The team figured that they had to discover a “small molecule glue” working as an “autophagosome tethering compound” (ATTEC), which could stick LC3 and mHTT together to load it onto autophagosomes for degradation. Importantly, this molecular glue should not bind the normal form of the HTT protein, “which has essential functions especially during development and young adulthood,” the researchers noted.

But finding such a compound was extremely challenging. One out of about 2,000 compounds has the desired properties, so identifying a particular group was a major obstacle in the project for a long time. The researchers had to develop fast, sensitive, and high-throughput screening chips and advanced optical technologies to single out four small molecules that could bind to both LC3 and mHTT.

In mouse and fly models of Huntington’s as well as in neurons derived from patient cells in the lab, very small amounts of these compounds were enough to significantly reduce the levels of mHTT, with little effect on normal HTT.

Even more promising, two of these compounds, given in small doses, were able to enter the brain and significantly reduce mHTT levels in the cortex and striatum (a region of the basal ganglia) of mice.

Importantly, the compounds significantly rescued Huntington’s-disease-like symptoms, namely behavioral deficits — supporting their therapeutic potential.

The researchers noted that this is “a proof-of-principle study, and further investigations will be required to establish the suitability for therapeutic application” — namely preclinical studies of efficacy and safety.

When the researchers discovered that ATTEC compounds were “glued” to mHTT through their long glutamine stretch (polyQ), they realized that this approach could be applied to other human diseases caused by mutant proteins containing long polyQ.

“These compounds may not only be effective in the treatment of Huntington’s disease but also applicable to other polyQ diseases,” study author Boxun Lu said in a press release. “The new concept of drug development using autophagosome-binding compounds (ATTEC) may also be applied to other pathogenic proteins that are undruggable, or even to pathogenic substances that are not proteins, such as organelles or lipids.”