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Molecules Engineered to Fight Alzheimer’s Disease and Other Neurodegenerative Disorders

By BiotechDaily International staff writers
Posted on 05 May 2014
Researchers have engineered a set of molecules with the potential to treat most neurodegenerative diseases that are characterized by misfolded proteins, such as Alzheimer’s, Parkinson’s, and Huntington’s diseases.

These molecules are based on what NeuroPhage Pharmaceuticals, Inc. (Cambridge, MA, USA), the developer of the technology, calls a general amyloid interaction motif (GAIM), which recognizes a characteristic that is typical to many toxic, misfolded proteins, not only one type of misfolded protein. This approach provides a range of therapeutic targets, so that a number of pathologies, such as amyloid beta plaques, tau tangles and alpha-synuclein Lewy bodies, can all be tackled simultaneously with a single drug candidate.

Moreover, GAIM molecules have been shown to not only prevent the formation of new toxic protein aggregates but can also dissipate existing aggregates in the form of both soluble oligomers and insoluble fibers, such as plaques and tangles.

“The research published […] describes GAIM, NeuroPhage’s unique approach to treat diseases characterized by misfolded proteins. GAIM has the potential to provide a more robust response than previous therapies because it enables the simultaneous targeting of multiple pathologies within a single disease,” said Dr. Richard Fisher, chief scientific officer at NeuroPhage. The findings of this technology were published online April 22, 2014, in the Journal of Molecular Biology. “Symptoms of neurodegenerative diseases often appear well after the troublesome aggregates have begun to accumulate in the brain. By then, therapies that only target newly forming aggregates are likely to only slow the progression of the disease and are believed to be too late once the aggregates are formed,” said Dr. Gregory A. Petsko, a professor of neurology at Weill Cornell Medical College (New York, NY, USA) and a professor of biochemistry and chemistry, at Brandeis University (Waltham, MA, USA). “Therapies based on GAIM would represent a completely new paradigm in the treatment of many neurodegenerative diseases with their potential to ameliorate existing symptoms and prevent disease progression. The hope is this will eventually lead to a real treatment for Alzheimer’s disease, but for now, the science behind it is quite compelling.”

Researchers used a range of techniques, including X-ray fiber diffraction and nuclear magnetic resonance spectroscopy (NMRS), to demonstrate the activities of GAIM. They found that GAIM effectively binds to multiple types of misfolded proteins during their formation in such a way that prevents new toxic protein aggregates from forming. Furthermore, upon incubating GAIM with various misfolded proteins, the researchers observed that GAIM disrupted these assemblies of misfolded proteins by causing a conformational alteration in their structures. This structural change could enable the body’s natural disposal processes to recognize and clear the misfolded proteins, which in principle, would enable the brain to return to a more normal state. The capability to destabilize pre-existing aggregates of multiple types of misfolded proteins is unique in the field.

The discovery of GAIM has led to the creation of NeuroPhage’s lead candidate, NPT088, which is the GAIM motif fused to a portion of a human antibody. The outcome is a potential therapeutic that can be simply delivered to patients. NeuroPhage has gathered extensive preclinical data on this candidate, showing its effectiveness across disease models of Alzheimer’s, Parkinson’s and related diseases characterized by aggregation of the tau protein. NeuroPhage expects that NPT088 will be ready for human studies in late 2015.

“With recent advances in imaging agents for beta-amyloid and tau in Alzheimer’s disease, we believe we should be able to demonstrate clinical proof of mechanism in a phase 1b study with NPT088,” said Jonathan Solomon, CEO at NeuroPhage. “If successful, we would then have the opportunity to pursue many therapeutic options in several neurodegenerative diseases of protein aggregation.”

NeuroPhage Pharmaceuticals has fusion-protein drug candidates in development for neurodegenerative diseases, many of which cause progressive mental decline and dementia. NeuroPhage is initially developing candidates to treat Alzheimer’s and Parkinson’s disease, in which a number of different misfolded proteins accumulate, acting jointly to additionally intensify disease progression.

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