2 small molecules ease symptoms, progression in mice, study finds

Oral treatments appear to suppress mutant huntingtin protein

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by Steve Bryson, PhD |

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Two types of orally available small molecules ameliorated symptoms and slowed progression of Huntington’s disease in a mouse model, a study reported.

The treatments effectively reduced the levels of the mutant huntingtin protein in the brain without affecting normal huntingtin. The mutant version causes Huntington’s, a neurodegenerative condition.

“Even though the aged mouse model simulated the disease at an advanced stage, the treatment succeeded in turning back the hands of time to some extent,” first author Anat Bahat, PhD, from the Weizmann Institute of Science in Israel, said in a press release.

“In behavior studies, we observed reduced levels of anxiety and improved balance and coordination in the treated mice,” Bahat said.

The study, “Lowering mutant huntingtin by small molecules relieves Huntington’s disease symptoms and progression,” was published in EMBO Molecular Medicine.

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High huntingtin protein levels in saliva linked to worse disease

In Huntington’s, defects in one of the two HTT gene copies lead to the production of an abnormally long huntingtin protein, which is prone to form clumps. Over time, these clumps are thought to build up and cause inflammation and damage to nerve cells, resulting in symptoms such as uncontrolled movements, cognitive impairment, and psychiatric problems.

While current treatments can help alleviate symptoms, they cannot halt or slow the disease’s progression. Several disease-modifying experimental therapies designed to lower the production of the mutant protein are under development, but their administration is invasive, entailing injection into either the spinal canal or the brain.

Rivka Dikstein, PhD, who like Bahat is from the Weizmann Institute of Science, and her team have now discovered two small molecules that can access the brain from the bloodstream and suppress the production of mutant huntingtin while leaving the healthy version untouched. These molecules can thus potentially alter Huntington’s progression when given orally or by injection.

“We were delighted to find that small molecules managed to reach the brain without undergoing changes and without disintegrating along the way,” Dikstein said. “While other experimental treatments require repeated brain or spinal surgery, these molecules, delivered orally or by means of an injection, could pave the way for an effective and safe treatment of Huntington’s disease.”

Their therapeutic target was Spt5, a protein component of a larger protein complex called RNA polymerase 2 (Pol 2). This complex transcribes a gene’s DNA sequence to messenger RNA (mRNA) — the molecule that serves as a template to make a protein.

In particular, the Spt5-Pol 2 complex is required for the production of mutant HTT mRNA and the abnormally long huntingtin protein. This complex also appears to regulate the production of proteins associated with inflammation.

Previously, Dikstein and colleagues identified several small molecules that selectively blocked certain functions of Spt5 — the so-called Spt5-Pol 2 inhibitors (SPIs). Among them, three specifically suppressed the production of mutant huntingtin without disrupting normal huntingtin and other inflammatory-related proteins.

Help from SPI-24 and SPI-77

In this study, the team examined a group of similar, more potent molecules and found two — SPI-24 and SPI-77 — using cells from a Huntington’s mouse model. Then, in cells derived from four different Huntington’s patients, the SPIs significantly reduced the production of the mutant protein without affecting the normal huntingtin protein.

When injected directly into the brain of a Huntington’s mouse model with advanced disease, SPI-24 and SPI-77 significantly lowered the levels of mutant HTT mRNA compared with regular HTT mRNA. SPIs also improved the function of energy-producing mitochondria and boosted BDNF mRNA levels, which are usually low in Huntington’s.

Although both treatments appeared to lessen Huntington’s-related anxiety in mice, only SPI-24 significantly improved motor coordination and balance.

When administered orally or by an under-the-skin (subcutaneous) injection, SPIs were found to access the brain and reduce the levels of mutant HTT mRNA while increasing the levels of BDNF.

Lastly, researchers administered SPI-24 orally over two months at a time point in mice that coincided with early disease in humans. Before treatment, mice showed signs of heightened anxiety, which returned to normal levels after treatment. Likewise, SPI-treated mice showed improved balance and less hyperactivity than untreated mice, which displayed worsening balance and hyperactivity.

“Our study demonstrated that lowering mutant Htt levels by small molecules targeting Spt5-Pol II represents a highly effective therapeutic approach for [Huntington’s],” the researchers wrote. “Due to their simple delivery, the SPIs are excellent candidates for further clinical evaluations as a potential therapy against [Huntington’s disease].”