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There have been hundreds of patients that have received AAV
and done well. So, we feel that AAV is still the safest and most
validated platform for in vivo gene therapy delivery.
There are many companies looking to improve AAV by
making better capsids-better tissue or cell-type specificity,
greater stability, and higher transduction capacity. There's a
lot of room for improvement. However, as the field moves
forward there are reasons to continue to explore nonviral
delivery options. The most obvious being that viral delivery can
elicit an immunogenic response that can lead to a safety issue.
It's less of a problem for our program because we're
administering our therapy centrally, which tends to significantly
reduce an immunologic response. But for systemic
delivery, immune and inflammatory responses to AAV
capsids are an important safety issue that the field will
continue to monitor closely. Nonviral delivery will evolve
over the coming years, but we want to get this into patients
as quickly as possible, and currently AAV vectors remain the
best delivery option for rapid advancement into the clinic.
To add to that, there are two significant advantages to
using AAV. We're able to target specific structures within
the CNS, where we can deliver this gene of interest. This
mitigates many toxicity concerns compared to systemic
approaches. The second advantage is in the durability
of expression. Given the relatively recent arrival
of gene-therapy, we don't have excellent data on how
durable gene expression is over the course of decades.
However, the data that we have generated suggests
long-term expression of the functional PSEN1 gene can
be achieved from a single injection.
Anjali Sarkar: What kind of customizations
are you exploring to promote target specificity
and durability?
We are administering the AAV directly into the central
nervous system and not looking to administer it systemically.
So, we do not need to cross the blood brain barrier, which
remains a challenge for the AAV field.
The combination of the promoter and the capsid
are the two key levers that will direct a gene therapy to
specific tissues and cell types. We're working on a specific
AAV capsid, which is effective at transducing neurons, the
cells that draw our primary interest. The other key lever is
the promoter that drives transgene expression. There are
certainly ways to target expression to specific cell types
using cell type-specific promoters. We have opted not to
do that because we're looking to get broad expression.
While we want to get expression in neurons, we think
expression in other brain cell types like glial cells is beneficial
or, at least, there is no downside to glial expression
that we are aware of. We're looking to drive high, broad,
and robust expression.
Anjali Sarkar: You mentioned direct injection
into the central nervous system. Does this
involve injection into the cerebrospinal fluid
(CSF) and require surgery?
Yes, it is currently a surgical procedure. Going into the CSF
is one option and going directly into brain tissue is the other
option. One can access the CSF compartment at several
locations, which will have a major impact on what cells are
transduced by the virus. However, going directly into brain
tissue is increasingly seen as an effective route for brain
delivery. First, it allows you to target the virus to the specific
region of interest, as opposed to bathing the brain, or the
body if you go in intravenously. Secondly, these viruses get
transported effectively once they're introduced into brain
tissue. An interesting observation made several years ago
is that viruses move along neuronal axons that connect
different parts of the brain. Administering the virus into one
part of the brain can result in the virus being transported
along axons to distal parts of the brain providing much
broader distribution. | 7


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