STAR Molecule Shows Promise in Cell Model of Alzheimer’s Disease

Patricia Inacio, PhD avatar

by Patricia Inacio, PhD |

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Gain Therapeutics‘ investigational STAR (small-molecule structurally targeted allosteric regulators) candidate lowered toxic amyloid-beta and tau protein levels, both hallmarks of Alzheimer’s disease, in a cellular model of the disease.

Treatment with the STAR molecule enhanced the survival and boosted communication between nerve cells, the company announced.

The results support the potential of STARs molecules for Alzheimer’s disease, after initial findings showed promise in Gain’s Parkinson’s disease program.

“The new data corroborate similar results we have recently published in our PD [Parkinson’s disease] program, and represent the first data showing a beneficial effect of our STAR compounds in an AD [Alzheimer’s disease] model,” Manolo Bellotto, PhD, president and general manager of Gain, said.

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“We are excited to present this data that provides further evidence of the significant therapeutic potential of our STAR small molecules in neurodegenerative diseases, including Parkinson’s and Alzheimer’s Disease,” Eric Richman, Gain’s CEO, said.

The results were presented in the poster, “Brain-penetrant Structurally targeted Allosteric Regulators for Glucocerebrosidase (GCase) Show Promising Pharmacological Activity in Models of Parkinson Disease” at the International Conference on Alzheimer’s and Parkinson’s Diseases (AD/PD 2022).

The enzyme beta-glucocerebrosidase (GCase) is an important component of cells’ recycling factories, called lysosomes.

Mutations in the GBA1 gene, which gives rise to GCase, are the most common genetic risk factor for Parkinson’s and result in a lack of or faulty activity of this enzyme. This leads to toxic substances accumulating inside cells, such as the alpha-synuclein protein, which is linked with the neurodegeneration seen in people with alpha-synucleinopathies, including Parkinson’s disease.

Despite not being much studied, reduced levels and activity of GCase are also involved in the accumulation of abnormal aggregates of amyloid-beta and tau proteins characteristic of Alzheimer’s disease.

Specifically, brain nerve cells of people with Alzheimer’s disease are enriched in a toxic form of amyloid beta, called amyloid beta 42, and hyperphosphorylated tau (pTau). These abnormal proteins are more prone to form toxic aggregates that cause the typical amyloid plaques and tangled tau fibers.

Gain Therapeutic’s  STARs were designed using Gain’s Site-directed Enzyme Enhancement Therapy (SEE-Tx) system. The platform uses the 3D structure of proteins to identify and predict the affinity of potential drug-binding sites.

This platform “is uniquely suited to identify novel allosteric binding sites and small molecule that regulate protein function,” Richman said.

Administered orally, STARs were designed to stabilize and increase GCase protein levels and their transport to lysosomes, raising the levels of GCase enzymatic activity.

Results revealed that treatment with the company’s STARs in a cellular model of Alzheimer’s decreased the neurotoxicity and inflammation that results when toxic species of amyloid-beta and tau accumulate. Treatment also promoted the survival of nerve cells and neurites, cell body extensions that nerve cells normally use to communicate with each other.

In a mouse model of Parkinson’s disease, treatment resulted in decreased neuroinflammation, lower levels of toxic alpha-synuclein and reduced motor deficits.

The new data “show that our STARs molecules, which stabilize wild-type GCase protein in a dose dependent-manner, promote depletion of [alpha]-synuclein toxic forms as well as … tau protein, thus improving key pathophysiological features in [Parkinson’s] and [Alzheimer’s], respectively,” Bellotto said.