Selphagy Therapeutics Works on LAMP2A Upregulation to Promote Autophagy

It has been more than a decade since researchers demonstrated that genetic engineering of mice to boost LAMP2A levels in the liver produced a sizable rejuvenation of liver function in old animals. This happens because increased levels of LAMP2A cause an upregulation of chaperone-mediated autophagy, a cellular maintenance process responsible for removing damaged molecules and structures in the cell. This makes cells more functional, and thus the tissue more functional. Since then, work on LAMP2A and autophagy has continued. Nowadays, the same research group that produced the liver results is a part of Selphagy Therapeutics within Life Biosciences, developing a small molecule approach to LAMP2A upregulation. This will inevitably be far less effective than gene therapy, but small molecules are still the way that most research programs move to the clinic, a function of the very conservative nature of venture funding and regulation in the biotech space.

All cells maintain a network of cleaning systems that remove and recycle unwanted proteins. One school of thought holds that when the process, called autophagy, malfunctions in neurons, the toxic buildup of proteins can promote neurodegenerative diseases such as Alzheimer's. Now, scientists have shown that a drug designed to invigorate a specialized cellular garbage disposal mechanism ameliorated symptoms in two mouse models of Alzheimer's.

The system the drug targets is called chaperone-mediated autophagy (CMA), in which single proteins are selected and escorted to spherical vesicles in cells called lysosomes, where they are then degraded. Once at the lysosome, the protein-chaperone complex binds to receptors called lysosome-associated membrane protein type 2A (LAMP2A) to trigger the destruction process. The drug, called CA, works by ramping up LAMP2A to boost CMA activity.

CMA activity normally drops as people age, but neurodegenerative disease can make it worse, further affecting the normal protein balance in the brain. The researchers tested whether a CMA activator like CA could protect against Alzheimer's. They gave the oral drug to mice that either had a tau abnormality or a combination of toxic tau and beta-amyloid protein clumps. The drug significantly reduced levels of tau and beta-amyloid, as well as plaques, in the brains of the animals. The treatment also normalized the animals' walking ability and improved visual memory, anxiety- and depression-like behaviors, and neuromuscular strength.



I'm still amazed at how the conversation between Dr. Tyrell and Roy Batty in the movie "Blade Runner" is a prophecy of much of this. What did Phillip K. Dick, Fancher, and People's know, or was it just inspired?

Posted by: Thomas Mark Schaefer at May 5th, 2021 7:50 AM

@Thomas. Because they said something about proteins? Hmm

Anyways this amazing research & it sounds like an amazing breakthrough.

Who could have known? If we wanted to brighten the mind, all we needed to do was switch on the LAMP2.

Posted by: Matt at May 5th, 2021 7:43 PM

Interesting... try googling: LAMP2A cancer

lots of articles implicating LAMP2A as part of how cancer cells metastasize.

Posted by: Matt Pease at May 5th, 2021 7:56 PM
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