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Next we list what could be the
most relevant to discuss, toxicity
concern when
using gene transfer.
Now most of the toxicity
which we'll discuss
first has to do with
in vivo gene therapy.
In which vector particles are
directly administered to tissues.
Because gene therapy usually entails
the administration of large amounts
of particles all together,
like a bolus of particles,
this is often a substantial
dose acutely administered.
It may trigger a number of
acute short term responses.
Particularly if the vector
is a viral vector, for which
the immune system, of
course, has usually
a good capacity to
sense and respond.
But also when using chemical or
some sort of lipid complexes of DNA.
Now some of these responses
are usually dose-dependent,
so they show the typical acute
toxicity-dependent on the dosing
of particles, and can be controlled
by identifying a safe interval
of doses, and the
minimally effective
and the maximally tolerated
doses as in most pharmacology.
Other responses on the other
and may be not dose-dependent.
They are acutely a type of allergic
response to some components,
and they may be more
difficult to control.
Most of the dose-dependent
allergic responses as mentioned
are triggered by innate cells
recognizing the vector particle
and releasing the
inflammatory sequence.
The key aspect of that recognition
are Toll-like receptors present
on the membrane, or in the
endosome or immune cell,
mostly innate immune
cells, in the body.
These are most often phagocytes
in the tissues, in the spleen,
in the liver.
As mentioned they are very
efficient at phagocytosis
of the administered particle.
And then the Toll-like receptor
may recognize in the particle which
is in the phagosome and partly
degraded in the phagosome, RNA,
ribosomal RNA, DNA-- which may have
unmethylated CPG-like plasmid DNA--
triggering a strong
innate immune reaction.
Other sensors are cytosolic
sensors, the RIG-I family.
And I mentioned this when I was
talking about uncoating before.
In which DNA or RNA may be
recognized in the cytosol as
of foreign origin,
because they for instance
don't have again
methylated CPG, or they
don't have a 5' cap
in the case of RNA.
And trigger innate activation,
interferon fear responses,
and so on.
Another type of toxicity may be
driven by components of the vector
particle itself, which may
exert some tissue toxicity.
For instance viral envelope,
which fuses to cell membrane,
can give rise to toxicity by
fusing cells to each other.
Especially when there is a lot
of viral particle administered.
So cells which are neighboring
cells exposed to high vector dose
may actually fuse to themselves.
And this is called also
fusion from without
and may give rise then to
toxicity and cell death.
Lipids themselves, or in some
cases viral proteins themselves,
like replicase or integrase, may
trigger toxicity into the cell.
