Compounds Targeting ß-Amyloid Ion Channels for Diagnosis and Treatment of Alzheimer’s Disease

Background: A number of neurological diseases, including Alzheimer’s (AD), Huntington’s, and Parkinson’s, are characterized by deposition of amyloid plaques. These beta sheet-rich structures, formed from the self-aggregation of specific proteins and peptides (e.g., beta-amyloid peptides in the case of AD), may contribute to the pathology of amyloid-based neurodegenerative diseases. Current therapeutic strategies for AD focus on:

Technology Description: UC San Diego researchers have used a validated, electrophysiological, proprietary screen to identify and analog several classes of molecules with excellent potential as lead compounds for therapeutic and imaging agents. These compounds bind strongly to beta-amyloid aggregates and have been shown to inhibit the ion channel activity of beta-amyloid oligomers. In addition, in-vitro studies have shown these compounds to be non-toxic in concentrations up to 100μM. Ongoing work is focused on evaluating the most promising compositions for their ability to inhibit beta-amyloid channel activity in primary neurons and for their efficacy in behavioral studies using mice.

Advantages: By obviating the need for specific fluorescent, spectroscopic, radioactive, and mechanistic properties, this approach is yielding classes of compounds more compatible with and readily translatable to clinical practice. Specifically, many of these proprietary compounds:

  • Have low molecular weight.
  • Have known and favorable pharmacokinetic properties.
  • Have known permeability across the blood-brain barrier.
  • Are commercially available.
  • Are FDA-approved drugs.
  • Satisfy the Lapinski rule of five.
  • Show concentration-dependent dose response in vitro.
  • May have utility as in vivo imaging agents for the diagnosis of AD.

Finally, while this approach has been developed using aggregated beta-amyloid peptides that are relevant to Alzheimer’s disease, the same screening methods may be adapted to identify therapeutic/diagnostic agents for other neurological diseases, including Parkinson’s, Huntington, Down’s Syndrome, bovine spongiform encephalopathy (mad cow disease), Kuru, Creutzfeldt-Jakob disease, and fatal familial insomnia.

Patent Information: U.S. patents are pending; see WO/2008/151073 and WO/2008/150467.

Related Materials:
The following are a list of references.

Also see related technology cases SD2006-104 and SD2007-056.

Keywords: amyloid, Aβ, fibril, aggregate, Parkinson’s, Huntington, Down’s, encephalopathy, spongiform, BSE, Kuru, Creutzfeldt, fatal familial insomnia, plaque, PET, drug

Case Number: SD2007-018

Inquiries To: invent@ucsd.edu