HT-ALZ Leads to Cognitive Improvements in Diseased Mice

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Chronic treatment with HT-ALZ, Hoth Therapeutics‘ investigational oral therapy for Alzheimer’s disease, led to significant cognitive improvements in a mouse model of the neurodegenerative condition.

The data were collected as part of Hoth’s ongoing sponsored research agreement with investigators at Washington University in St. Louis, Missouri, led by Carla Yuede, PhD, and John Cirrito, PhD. Yuede is an associate professor of psychiatry, and Cirrito is an associate professor of neurology, at the Washington University School of Medicine.

“The results support the therapeutic potential of HT-ALZ to provide cognitive improvement as an [Alzheimer’s disease] therapeutic,” Hoth wrote in a press release.

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Alzheimer’s is marked by the abnormal and toxic accumulation of amyloid-beta and tau proteins in the brain, leading to disrupted nerve cell communication that drives the neurodegenerative disease’s hallmark symptoms of dementia, including memory loss, confusion and other cognitive problems.

Hoth is developing HT-ALZ  for the treatment of dementia associated with Alzheimer’s disease. Initial work from scientists at Washington University evaluated the effects of oral HT-ALZ administered to APP/PS1+/- mice, a mouse model of Alzheimer’s in which animals are genetically engineered to carry two mutations associated with early-onset Alzheimer’s in patients.

Results showed that HT-ALZ lowered levels of amyloid-beta clumps in the brains of both male and female mice compared with their own pre-treatment levels, as well as compared with mice given a sham treatment without medication.

Hoth and the university recently announced the research agreement would be extended, with learning and memory tests after treatment comprising part of the planned experiments.

Hoth reports outcomes

Hoth now reports positive outcomes from these ongoing experiments. The effects of chronic HT-ALZ treatment on a battery of behavioral assessments aimed at monitoring cognition, learning and memory were evaluated against a sham treatment in the APP/PS1+/- model.

The behavior of the treated APP/PS1+/- mice also were compared to that in normal mice without signs of Alzheimer’s, called wild-type mice.

Tests included pre-pulse inhibition, which measures the ability to filter out relevant information and novel object recognition, a recognition memory test. The mice also underwent cued and contextual fear conditioning — tests that  assess the ability to learn to associate an aversive stimulus with particular environments or cues.

According to Hoth, mice treated for at least five weeks showed significant improvements in all of the behavioral tests compared with mice that were given the vehicle. The behavioral performance in treated mice showed similar trends compared with wild-type animals.

“Chronic dosing had a significant effect on four behavioral deficits that these mice develop due to [amyloid-beta] pathology,” Cirrito said. “Such results provide confidence that the investigational treatment is having a meaningful impact in the brain.”

Other behavioral tests performed earlier than five weeks did not show significant improvements, but trends toward improvement were observed, suggesting a time-dependent effect of the treatment similar to those observed with other therapeutics, Hoth Therapeutics noted in the release. Those tests will now be repeated after longer dosing periods.

Future studies conducted by the Washington University researchers will evaluate the effect of HT-ALZ on memory, anxiety and executive function — a group of skills involved in performing everyday functions — after six weeks of treatment at four different dose levels.

The goal of these experiments is to understand if there is a dose-dependent response to the treatment that might inform dose selection for future in-human clinical trials.