Alzheimer’s disease has long been associated with the harmful
proteins amyloid beta and tau. They clump up in the brain, disrupting
neurons and causing memory loss and other symptoms. Researchers at
Temple University’s Lewis Katz School of Medicine say they’ve found a
new way to prevent amyloid beta and tau from building up in the brain.
The Temple team invented a drug that helps brain cells recognize
defective proteins so they can stabilize or remove them altogether
before they form toxic clumps. In mouse models of Alzheimer’s, animals
who received the drug prior to developing symptoms experienced decreases
in tau tangles and amyloid plaques, the researchers
reported in the journal Molecular Neurodegeneration.
The researchers refer to their drug as a “chaperone,” because it’s
designed to boost levels of a molecule that’s key to cells’ ability to
sort and move proteins. That molecule, VPS35, separates dysfunctional
proteins and moves them out of cellular compartments called endosomes so
they can be discarded.
Previous research from Temple revealed that levels of VPS35 fall in
Alzheimer’s disease. They linked that decline with the formation of tau
tangles inside of neurons and amyloid plaques outside of them.
The drug chaperone, dubbed TPT-172, replenished levels of VPS35 in
the mouse models. That restored the functioning of synapses, which are
the places neurons connect and share information. The mice treated with
the drug showed improvements in memory and behavior as compared to
animals that were also destined to develop Alzheimer’s but were given no
treatment. The researchers reported that the Alzheimer’s models that
received TPT-172 behaved like normal, wild mice.
Drugs targeting amyloid in Alzheimer’s have so far proven
disappointing, but combating toxic brain plaques is still an approach
several biotechs are pursuing. Among them is T3D Therapeutics, which
raised $15 million in a series B round late last year to develop a drug
that addresses protein misfolding in the brain by correcting improper
glucose and fat metabolism.
In December, Biogen
paid
$45 million to license an antisense treatment from Ionis that’s
designed to reduce the production of tau protein. That drug is currently
in phase 1 testing. And Biogen hasn’t given up on its amyloid-targeted
drug aducanumab, even though an initial analysis of the phase 3 program
questioned whether it would ultimately succeed.
Unlike other investigational therapies that are designed to block
proteins, TPT-172 targets a cellular mechanism, which could help limit
the potential side effects, argued Domenico Praticò, M.D., professor and
director of Temple’s Alzheimer’s Center, in a
statement. That adds “to the appeal of pursuing pharmacological chaperone drugs as novel Alzheimer’s treatments,” he said.
The next step for Praticò’s team is to test TPT-17 in older mice.
“Because our most recent investigation was a preventative study, we want
to know now whether this therapy could also work as a treatment for
patients already diagnosed with Alzheimer’s disease,” he said.
https://www.fiercebiotech.com/research/drug-chaperone-fends-off-alzheimer-s-mice-by-preventing-toxic-protein-clumping
