Neugeneron - Neurodegenerative diseases

Our own research and research by other prominent laboratories has identified targets that play pivotal roles in the neurodegenerative diseases. Seperate efforts have identified targets in glioblastoma. We are developing brain-permeable chemical drugs that modulate the activity of these targets.

Neudegenerative diseases

Glioblastoma

Our Progress

Neugeneron is focusing on two specific neurodegenerative diseases - Alzheimer’s disease and Huntington’s disease

Alzheimer’s disease

Alzheimer’s disease is a progressive brain disorder in which neuronal cells that control memory and thinking skills die causing dementia and rendering the affected individual incapable of carrying out simple tasks. It is estimated that close to 6 million Americans, most of them age 65 or older, have dementia caused by Alzheimer’s disease. Brains of patients with Alzheimer’s disease reveal three characteristic features that define the disease – accumulation and aggregation of a protein called Aβ outside neuronal cells, aggregation of a protein called tau inside neuronal cells, and subsequently the loss of neuronal cells in specific brain regions. Most current efforts at developing a treatment for Alzheimer’s disease are targeted towards reducing Aβ or tau production, preventing their aggregation, or boosting their clearance from the brain. However, many studies have established that cognitive impairment in Alzheimer’s disease begins several years before issues with Aβ and tau occur indicating that other alterations may initiate cognitive deficits and facilitate the aggregation of Aβ and tau, which then produces the full-blown disease. It is noteworthy that none of the many clinical trials targeting Aβ and tau that have been conducted so far have shown efficacy suggesting that consistent with the idea that changes to Aβ and tau may be necessary for disease progression but that other alterations trigger disease initiation. Neugeneron is pursuing the hypothesis that activation of specific protein kinases (enzymes that add phosphate groups to proteins affecting their function either positively or negatively) trigger the onset of AD as well as progression of the disease.

Neugeneron compound HSB-13 targets three different enzymes which all become overactive in the brains of patients with Alzheimer’s disease – Glycogen Synthase Kinase-3 (GSK-3), p38 MAP Kinase, and specific Cyclin-Dependent Kinases (CDKs). Each of these enzymes contribute to the abnormalities in Aβ and tau and inhibiting each of these three enzymes has been shown to be protective (prevent Aβ and tau pathology) and improve cognitive performance in mouse models of Alzheimer’s disease. Besides their detrimental effects on Aβ and tau, each of this trifecta of enzymes directly contributes to the killing of the neuronal cell. In addition to affecting events within neurons, p38 MAP Kinase plays a central role in promoting an inflammatory response outside of the neuron that exacerbates neuronal loss in the Alzheimer’s brain.

We have previously described that HSB-13 administration improves survival in a Drosophila (fly) model of Alzheimer’s disease.

Huntington’s disease

Huntington's disease is a rare, inherited disorder that is caused by an expansion of a DNA tract in the huntingtin gene that results in the production of an abnormal form of the huntingtin protein. The mutant huntingtin protein aggregates in the brain and causes the death of neuronal cells largely, but not solely, in a brain region called the striatum. Huntington’s disease display severe impairment in voluntary movement as well as cognitive deficits and psychiatric disturbances. Huntington's disease symptoms often first appear when people are in their 30s or 40s. Although there are medications that alleviate some of the symptoms, there are no treatments that reduce the loss of neuronal cells in Huntington’s disease or that are able of extending the life-span of patients.

Scientists have spent a considerable amount of effort over the past three decades trying to understand why neurons die in the brains of Huntington’s disease patients. The consensus from these studies is that the abnormal, mutant form of the huntingtin protein converts a beneficial protein into a neurotoxic one. Several studies conducted in cell culture or mouse models of Huntington’s disease have demonstrated that inhibitors of Glycogen Synthase Kinase-3 (GSK-3), p38 MAP Kinase, and specific Cyclin-Dependent Kinases (CDKs) can protect neurons from the toxicity of the mutant huntington protein.

We have previously described that administration of HSB13, which inhibits all three of these kinases, prevents neuronal loss and reduced behavioral deficits in a mouse model of Huntington’s disease.