Various forms of amyloid build up in tissues with age, forming fibrils and clumps. These are precipitates of misfolded proteins, and while the harm caused by amyloids is not fully understood in all cases they are associated with numerous specific diseases of aging. The amyloid plaques that accompany Alzheimer's disease are perhaps the best known, for example.
It is thought that the oldest people, those who live longer than 110 years of age, are largely felled in end by senile systemic amyloidosis which involves amyloids formed of misfolded transthyretin. There is also a rare genetic disease in which this occurs early in life, called transthyretin-related hereditary amyloidosis or familial amyloidotic polyneuropathy - and as is often the case in such matters research into the rare genetic disease has more funding than research into the common age-related condition. Fortunately any potential treatment involving removal of amyloid is directly applicable to both types of condition.
Transthyretin (TTR) amyloidoses comprise a wide spectrum of acquired and hereditary diseases triggered by extracellular deposition of toxic TTR aggregates in various organs. Despite recent advances regarding the elucidation of the molecular mechanisms underlying TTR misfolding and pathogenic self-assembly, there is still no effective therapy for treatment of these fatal disorders.
Recently, the "molecular tweezers", CLR01, has been reported to inhibit self-assembly and toxicity of different amyloidogenic proteins in vitro, including TTR, by interfering with hydrophobic and electrostatic interactions known to play an important role in the aggregation process. In addition, CLR01 showed therapeutic effects in animal models of Alzheimer's disease and Parkinson's disease. Here, we assessed the ability of CLR01 to modulate TTR misfolding and aggregation in cell culture and in an animal model.
In cell culture assays we found that CLR01 inhibited TTR oligomerization [and] alleviated TTR-induced neurotoxicity by redirecting TTR aggregation into the formation of innocuous assemblies. To determine whether CLR01 was effective in vivo, we tested the compound in mice expressing TTR V30M, a model of familial amyloidotic polyneuropathy, which recapitulates the main pathological features of the human disease. Immunohistochemical and Western blot analyses showed a significant decrease in TTR burden in the gastrointestinal tract and the peripheral nervous system in mice treated with CLR01, with a concomitant reduction in aggregate-induced endoplasmic reticulum stress response, protein oxidation, and apoptosis. Taken together, our preclinical data suggest that CLR01 is a promising lead compound for development of innovative, disease-modifying therapy for TTR amyloidosis.