Oral compound targeting toxic proteins may be a new Huntington’s treatment
In lab models, compound lessened brain shrinkage, improved movement
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An oral compound now being tested as a potential treatment for several neurodegenerative conditions was shown, in multiple laboratory models, to reduce the toxic protein clumps in nerve cells that drive Huntington’s disease.
These findings suggest that the compound, called Anle138b, may also be a possible therapeutic option for people with this rare genetic disorder, according to the research team, from institutions in Germany.
In Huntington’s animal and cell models, anle138b reduced harmful clumps, or aggregates, of proteins known to underlie the disease, the data showed. The compound also lessened brain shrinkage and inflammation, improved movement, and modestly extended lifespan in mice, the researchers noted.
“Our data show that specifically targeting toxic protein aggregates with the compound anle138b is a promising approach for stabilizing neuronal health in the long term,” Irina Dudanova, PhD, study lead at the University of Würzburg, said in a university news story detailing the findings.
Per the researchers: “Altogether these results illustrate the potential of anle138b as a disease-modifying treatment for [Huntington’s].”
The study, “Anle138b ameliorates pathological phenotypes in mouse and cellular models of Huntington’s disease,” was published in the journal EMBO Molecular Medicine.
An inherited brain disorder, Huntington’s is characterized by the production of a misshapen form of the huntingtin protein, known as mutant huntingtin (mHTT). This form of faulty huntingtin forms clumps that damage brain cells and drive disease symptoms.
Compound first tested in trials for Parkinson’s, other conditions
Anle138b, also known as emrusolmin, was originally identified for its ability to block the formation of harmful protein clumps in other diseases, such as Parkinson’s disease. It works by attaching to small, toxic clusters of misfolded proteins, called oligomers, before they grow into larger aggregates. Anle138b can be taken by mouth and reaches the brain.
In a Phase 1 clinical trial, anle138b demonstrated a good safety and tolerability profile in humans at doses exceeding those required for full effectiveness in mouse models. A Phase 2 trial testing the potential drug in another neurodegenerative condition, called multiple system atrophy, is now underway.
Because the therapeutic potential of anle138b for people with Huntington’s has yet to be explored, Dudanova’s team first assessed its effects on mouse brain cells engineered to produce mHTT.
Adding the compound to these cells improved their survival and reduced the fraction of cells containing visible mHTT aggregates. Anle138b also corrected problems with proteostasis, the mechanism by which cells maintain proteins in a correctly folded and functional state.
Building on these findings, the team gave anle138b to R6/2 mice, a commonly used model of Huntington’s that develops symptoms quickly, beginning at conception.
By 12 weeks of age, anle138b-treated mice showed improvements across several measures of movement, including grip strength, balance and coordination, and general activity. The mice also showed less limb clasping, a behavior often seen in Huntington’s mouse models. While treatment modestly extended lifespan by an average of five days, this benefit was limited to female mice. Still, the treatment had no detectable negative effects in disease-free mice.
At the brain level, anle138b-treated R6/2 mice showed less shrinkage of the forebrain and less enlargement of the brain’s fluid-filled cavities (ventricles) than untreated Huntington’s mice. The treatment also reduced markers of neuroinflammation, reduced the proportion of neurons containing mHTT clumps, and lowered levels of aggregated mHTT, according to the researchers.
Levels of two proteins that typically decline in Huntington’s, PDE10A and DARPP-32, were also restored toward normal levels in treated mice, data showed.
“If PDE10A levels drop, that is a clear signal that the disease is progressing,” said Miguel da Silva Padilha, a doctoral student at the University of Würzburg and the study’s first author. “The protein is therefore well-suited as a biomarker for Huntington’s disease.”
Finally, anle138b reduced the loss of small protrusions on neurons called dendritic spines, as well as the loss of connections between neurons known as synapses, both of which are commonly reduced in Huntington’s.
Lab testing used stem cells from 2 people with Huntington’s
The researchers then tested anle138b in a second mouse model (zQ175DN), which develops a milder, slower form of disease more similar to adult-onset Huntington’s in people.
Beginning at four months of age, anle138b reduced the amount of aggregated mHTT in the motor cortex, a region of the brain that controls voluntary movement and is affected in Huntington’s. The treatment also prevented the decline in PDE10A protein levels observed in untreated zQ175DN mice.
To test relevance to humans, the team used stem cells derived from two Huntington’s patients, called induced pluripotent stem cells, and converted them into neural precursor cells, a type of early brain cell. Anle138b prevented the induced aggregation of mHTT in both cell lines, including one from a patient with more severe disease, the researchers noted.
The treatment had beneficial effects not only when administered throughout embryonic development and postnatal life, but also when started at an adult age.
Overall, “our results provide evidence of the promise of anle138b as a disease-modifying therapy for [Huntington’s disease],” the team wrote, noting that “the treatment had beneficial effects not only when administered throughout embryonic development and postnatal life, but also when started at an adult age.”
Dudanova noted that, “in our experiments … we also observed that the addition of anle138b reduced the amount of huntingtin aggregates.”
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