More on Molecular Tweezers to Treat Amyloid Accumulation

Amyloids are misfolded proteins that gather to form solid aggregates in tissues. Their presence grows with age and some types of amyloid are known to contribute to the pathology of specific age-related conditions: amyloid-β in Alzheimer's disease and misfolded transthyretin in senile systemic amyloidosis for example. Any potential rejuvenation toolkit must include a reliable technology platform for clearance of the various forms of amyloid. Of late researchers have been working on the use of what they call molecular tweezers for this purpose, and seem to be making meaningful progress:

An international team of more than 18 research groups has demonstrated that the compounds they developed can safely prevent harmful protein aggregation in preliminary tests using animals. The findings raise hope that a new class of drugs may be on the horizon for the more than 30 diseases and conditions that involve protein aggregation, including diabetes, cancer, spinal cord injury, Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS). Proteins are necessary for almost every cellular process. However, when cell machinery doesn't clear out old proteins, they can clump, or aggregate, into toxic plaques that lead to disease.

The researchers call the compounds that they developed molecular tweezers because of the way they wrap around the lysine amino acid chains that make up most proteins. The compounds are unique in their ability to attack only aggregated proteins, leaving healthy proteins alone. To develop a new drug, researchers typically screen large libraries of compounds to find ones that affect a protein involved in a disease. This team used a fundamentally different approach to develop the molecular tweezers. "We looked at the molecular and atomic interactions of proteins to understand what leads to their abnormal clumping. Then, we developed a tailored solution. So unlike many other drugs, we understand how and why our drug works."

The team is in the process of testing multiple versions of the tweezers, each with a slightly different molecular makeup. For CLR01, one of the most promising versions, the researchers have demonstrated therapeutic benefits in two rodent models of Alzheimer's disease, two fish and one mouse model of Parkinson's disease, a fish model of spinal cord injury and a mouse model of familial amyloidotic polyneuropathy, a rare disease in which protein aggregation affects the nervous system, heart and kidneys. "Our data suggest that CLR01, or a derivative thereof, may become a drug for a number of diseases that involve protein aggregation. We also found a high safety window for CLR01." In one of the safety tests, mice receiving a daily CLR01 dose 250 times higher than the therapeutic dose for one month showed no behavioral or physiological signs of distress or damage. In fact, blood cholesterol in the mice dropped by 40 percent, a possible positive side effect of CLR01.



The question is whether or not GlaxoSmithKline, Johnson & Johnson and others are aware of the SENS approach to clearing amyloid. The 2nd annual Rejuvenation Conference will be coming up in August and both of these companies plus Biogen, Lilly, and Pfizer mentioned in Jim's article should be invited to attend.

Posted by: Morpheus at March 31st, 2015 9:19 PM

In a slightly circular argument, if Glaxo and J&J were aware of the SENS sponsored approach to amyloid, then would the SENS foundation bother sponsoring it?

Posted by: Jim at April 1st, 2015 12:58 AM

The Glaxo news has just become public knowledge recently so SENS might have been unaware of their interest. Also, it may take more than one approach to clearing amyloid, transthyretin, and other aggregates. No one will know which one will pan out in the end until more time and money is spent on further trials in higher animals. Meanwhile, if even one Big Pharma company takes an interest in a SENS approach, funding could flow like water. SENS could sponsor other neglected areas and even profit if it could ultimately license an amyloid technology. Much has been written about the lack of visible progress and latching on to free enterprise at the RB Conference could remedy this. Someone over at SENS should definitely send an invite to these companies with as many others as possible to maximize interest in a strategic partnership.

Posted by: Morpheus at April 1st, 2015 12:00 PM

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