ChasRiver_Aug2022_Perspectives-Toward-a-Treatment - 10

PERSPECTIVES
stages of determining where we should be delivering this
in the brain, how much we should be delivering, and even
which vectors we should choose to be our lead candidates.
With this escalating approach we've built a high-quality
efficacy data package, from delivery, to target engagement,
and finally through proof-of-concept and preclinical efficacy.
We are now relying on nonhuman primate studies to understand
more about distribution and toxicity in that context.
This entire approach has been supplemented in parallel
by a substantial amount of in vitro data, which has informed
our in vivo approach. Our in vitro studies establish the basic
biological mechanisms of ADAD pathology, and how much
of our therapeutic is required to drive replacement of the
mutant gene. We've been able to drive a lot of high-quality
data using induced pluripotent stem cells (iPSCs). We're
currently working on understanding how our therapeutic
drives the normalization of γ-secretase function within the
context of mature iPSC-derived neurons.
Working with Holden's team has expanded our
bandwidth to allow Paros to maintain focus on its critical
internal research efforts while achieving exceptional in vivo
results to support our preclinical data package.
Anjali Sarkar: Are there any tools and
resources, such as brain atlases and connectivity
maps, that you use to determine the location
and dosage of the injections in mice?
HOLDEN JANSSENS:
There is a standard brain atlas that is commonly used in the
CNS field to determine what coordinates to target for select
brain regions. This " map " allows us to sterotaxically inject
in discrete brain regions and be consistent between animals
and across studies. If you're looking to see distribution, it's
important that you're injecting in the exact same spot every
single time to compare different AAVs, titers, and routes
of administration. Having that high level of accuracy and
precision is critical.
10 | GENengnews.com
" Time is the most valuable commodity in life
and certainly in the business world. Being
able to limit the amount of time we spend
on communication and establishing new
relationships is a huge benefit to us. "
- Eric Schaeffer
Anjali Sarkar: In addition to using amyloid,
and restoring functional γ-secretase, what other
readouts or biomarkers are you looking at as
landmarks of disease progression and
therapeutic efficacy?
BEN MOORE:
Biomarker development and understanding how our therapeutic
approach can modulate key biomarkers is a major
part of Paros Bio's preclinical program. We've built a robust
internal program-from in vitro to in vivo-to understand
how administering our therapeutic modulates and normalizes
neurodegenerative biomarkers.
Anjali Sarkar: Do you foresee recruiting
patients for the PSEN1 clinical trial to be
challenging considering the rareness of
the disease?
ERIC SCHAEFFER:
ADAD is rare but it's a well-studied disease. There are
ADAD patient advocacy groups, patient registries, and
organizations like the DIAN network that have extensive
experience in working in this patient population. We've
already started to reach out to some of the leading ADAD
organizations to help us identify patients, structure clinical
trials, and try to get the right patients willing to enter clinical
trials as soon as possible.
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ChasRiver_Aug2022_Perspectives-Toward-a-Treatment

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