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much younger adults who, if they're willing to be genetically
screened, can be identified as harboring a mutation that
will ultimately lead to ADAD. Of course, it's the patients'
decision whether they want to pursue treatment, but it opens
the possibility of treating them much earlier when they have
healthier brain function, and the possibility of an effective
treatment is much greater.
Anjali Sarkar: Is this ADAD gene therapy
Paros Bio's first step in a series of other
AD targeting approaches?
Right now, we're focused on our first program. We're a small
company and it's important for us to direct our resources to
what we think is an excellent target, probably the best target
for ADAD. But we certainly have earlier stage, exploratory
discovery programs that we're considering that could either
be directed towards genetic forms of AD or that go after
other underlying risk genes of late-onset AD. As our company
moves our lead program into the clinic, we'll be able to free up
resources to start to work on some of those earlier stage ideas.
Part 2
Targeting presenilin1:
Research, therapeutic
rationale, and biomarkers
Anjali Sarkar: The role of amyloid deposition
in AD etiology is controversial. What is the
scientific rationale behind Paros' strategy of
reinstating normal PSEN1 through gene
therapy to treat ADAD?
We acknowledge the controversial role of amyloid deposition
in the genesis of the disease. Our therapeutic approach
is conceptually quite straightforward. We understand that
ADAD is predominantly caused by mutations in one gene,
6 |
PSEN1. These mutations have a 100% prevalence: every
patient who has these mutations will go on to develop the
disease. So, while we pay close attention to the impact of our
therapeutic on amyloid deposition, especially given its utility
as a functional and well-characterized biomarker, that's
not necessarily our therapeutic approach. Our approach
is a gene replacement strategy to insert a wildtype form of
PSEN1 in place of the mutant. This approach is relatively
agnostic to amyloid deposition as cleavage of any γ-secretase
substrate would be normalized by replacing mutant PSEN1
with its wildtype form.
Anjali Sarkar: What are the advantages of
targeting PSEN1 over other treatment strategies
that are being investigated and how generalizable
will this treatment be for other forms of AD?
Currently, the number of disease-modifying therapeutic
approaches in the pipeline are quite limited, and we're
working to generate one of the first. A significant advantage
to our approach is that we can identify relatively homogenous
patient populations with a high degree of accuracy
because of the genetic determinants of ADAD. The strength
of this strategy lies in our deep understanding of the pathological
mechanism, and our targeted approach to intervene
directly in that mechanism.
Anjali Sarkar: You're using adeno-associated
virus (AAV) to introduce a wildtype human PSEN1
gene into ADAD patients. What is your take on
the challenges of using a viral delivery platform?
Did you consider other platforms? What were
your reasons for choosing AAV delivery?
While there are many nonviral delivery platforms in development,
these are generally not yet ready for clinical application.
Overwhelmingly, the gene therapy field is focused on AAV
and lentivirus as the main delivery platforms. I suspect it will
be that way for a while. AAV has an excellent safety record.


Table of Contents for the Digital Edition of ChasRiver_Aug2022_Perspectives-Toward-a-Treatment

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