Università Cattolica del Sacro Cuore

Clear the way to healthy ageing - issue#1

Many age related diseases still have no cure. Protein “debris” affects healthy cell functions: a new therapeutic strategy shows to be effective on different disease models.

by  Prof. Gal Bitan


“May you have a long and prosperous life” we wish each other on birthdays and other happy occasions. Indeed, in recent decades, human lifespan has been increasing steadily thanks to advances in modern medicine. Simply extending life, however, can be a double-edged sword if we are not careful to improve the quality of life in old age. Some people age gracefully and enjoy many years of health and clear mind, but unfortunately, they are a minority. For most, aging means an increase in health problems that can range from mild to devastating.

Perhaps the most feared condition of all is dementia, which in the vast majority of cases is strongly linked to aging. Frontotemporal dementia can occur relatively early, hitting people in their 50s. At age 60, the incidence of Alzheimer’s disease is approximately 1%, but the probability then doubles every five years, which means that by the mid-80’s, it reaches nearly 50%. And for those who escaped Alzheimer’s awaits Senile Systemic Amyloidosis, one of the main killers of super-centenarians.

A common pathologic mechanism underlying these diseases and over 30 others is the accumulation of protein “debris” in our cells. For healthy function, cells must constantly produce fresh proteins and break down old ones. With aging, the clearance mechanisms slowly deteriorate and if they can no longer cope, proteins begin to accumulate. Accumulation leads to abnormal sticking of the protein molecules to each other and formation of toxic clumps. Certain proteins are particularly prone to forming these toxic clumps, and the resulting disease depends on the particular protein and the specific cells attacked by each protein. For example, in Frontotemporal dementia the toxic clumps are made of a protein called tau, whereas in Alzheimer’s disease the pathology involves two types of toxic clumps – one made of tau and the other of the protein amyloid-beta. Toxic clumps of the protein transthyretin are the cause of Senile Systemic Amyloidosis and certain rare, familial diseases that affect populations in Portugal and Sweden. Yet other proteins form toxic clumps and cause British and Danish Dementia, Hereditary Finnish and Icelandic amyloidosis, and Familial Mediterranean Fever.

Currently, none of these diseases have a cure. Alzheimer’s disease alone affects over 35 million people worldwide and threatens to bankrupt the world’s economy by the middle of the century if no cure is found. Thus far, attempts to discover and develop drugs for these diseases have not been successful, likely because the phenomenon of protein clumping is distinct from typical drug targets. To address this major challenge, we have been developing a novel therapeutic strategy based on compounds called “molecular tweezers”. These compounds use a unique mechanism to prevent the formation of toxic clumps and enhance the clearance of the cellular protein debris. Importantly, the strategy is not limited to one particular protein, but rather targets the abnormal process of protein clumping itself and therefore is applicable to multiple diseases.

Our lead drug candidate, called CLR01, has been found to be effective against at least 14 different proteins, each of which causes a different disease. Pre-clinical experiments showed that CLR01 was effective in disease models of Alzheimer’s, Parkinson’s, and Familial Amyloid Polyneuropathy – one of the diseases caused by toxic clumps of transthyretin. A recent study also showed that in pre-clinical models, CLR01 was safe and well tolerated, providing important support for its future development toward human therapy.

The development of the “molecular tweezers” therapy has been carried out as a collaborative project named Breakthrough Treatment for Degenerative Diseases (BTDD), which involves over 30 laboratories around the world. A highly productive contributor to the project is the research group of Professor Claudio Grassi at the Università Cattolica del Sacro Cuore di Roma. Our collaboration with the Grassi group began in studies revealing important aspects of the way free radicals and oxidants participate in Alzheimer’s disease, and moved on to detailed characterization of the therapeutic effect of CLR01 in pre-clinical models of Alzheimer’s. We look forward to continuing this work and hope that the fruits of the BTDD project will be new medications that will clear cellular rubble, maintain healthy cellular function for many years, and allow people to remain happy and productive into their eighties, nineties, and beyond.