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PERSPECTIVES
An Expert Panel Discussion
MODERATOR:
Anjali A. Sarkar, PhD, Science Editor, GEN
Part 1
Paros Bio: History, vision,
and therapeutic pipeline
Anjali Sarkar: What is the science that led
to the founding of Paros Bio?
ERIC SCHAEFFER:
AD was first described in the early 20th century by Alois
Alzheimer and has been studied for many decades. It has
been challenging to understand the causes of the disease and
consequently, the best therapeutic approaches. The original
description of AD included clinical symptoms of cognitive
impairment and hallmark brain pathology which focused
on amyloid plaques and neurofibrillary tangles. Much of
the research that followed was directed towards trying to
understand molecular constituents of these pathologies and
how they might cause the disease.
In more recent decades there has been the development of
the " amyloid hypothesis, " which assumes that the disease is
potentially caused by overproduction of amyloid peptides.
One would presume that if there's too much amyloid in
the brain, the way to help patients would be to decrease it,
either by inhibiting the enzymes that form amyloid, or to use
antibodies to clear out amyloid that has already accumulated
in the brain. That was the mindset of the field for
decades, and many pharmaceutical companies have spent
significant time and funding pursuing these approaches.
About 25 years ago rare genetic mutations were discovered
that cause AD, but much earlier in life than the more
common, sporadic form of the disease. These are patients
with specific mutations that result in the development of the
typical symptoms of AD including deterioration of cognitive
4 | GENengnews.com
function and dementia, as early as their 30s and 40s, as
opposed to the much more common late-onset disease,
which typically occurs in patients in their 70s and 80s. As
those mutations were studied, it was understood that the
genes that contained those mutations were involved in the
generation of Aβ peptides, which are the main constituents
of amyloid plaques. This further reinforced the notion that
amyloid plaque formation was the underlying cause of AD.
The founders of our company, Raymond Kelleher, a
neurologist and scientist at Mass General Hospital and Jie
Shen, a professor of neurology at Harvard Medical School,
have spent more than two decades studying the presenilin
gene, one of the three genes associated with autosomal
dominant AD, and trying to understand the effect of
pathogenic mutations on gene function. Their work led the
field to understand that the mutations were not increasing
the production of Aβ peptides but contrary to the prevailing
hypothesis, were actually resulting in a partial loss of
function in the γ-secretase protease that generates amyloid
peptides. This caused a big shift in how the field thought
about the role of amyloid in AD and the kinds of therapeutic
strategies that might slow disease progression.
Now we get to our company, Paros Bio. If one works on
the assumption that these mutations are causing a partial
loss of γ-secretase function, then to treat the disease, one
will logically want to increase the function of the enzyme
as opposed to inhibiting it. That's the crux of what led to
the formation of our company and the science behind it.
Since patients have a dysfunctional form of the presenilin1
(PSEN1) protein, our strategy is to use gene therapy
to introduce a wildtype copy of the gene to see if that can
correct the enzyme dysfunction.
Anjali Sarkar: What is the mission and the
vision that drives Paros Bio?
ERIC SCHAEFFER:
The mission of our company is to help patients. That's at
the core of what drives all of us. This is a terrible disease.
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ChasRiver_Aug2022_Perspectives-Toward-a-Treatment

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