Jax Labs eBook - 23


Tayebi and colleagues crossed a mouse
model of Gaucher disease with mutations
in the Gba1 gene to a well-characterized
model of Parkinson's disease, showing
a direct link between GBA1 and the
synucleinopathies, and opening the path
to a new investigative direction for this
class of diseases (Tayebi et al., 2017).
The development of rare disease
therapies relies heavily on safety and
efficacy data generated in animal models.
If incorrect or suboptimal models are
used, or the in vivo experiments are not
correctly designed, the value of the data
generated in the preclinical phase is
limited, and results have low
translational value.
Unfortunately, the use of suboptimal
mouse models affects a non-negligible
number of published studies. The TDP-43
transgenic model of ALS represents
an informative example of a preclinical
mouse model that did not live up to the
23 | GENengnews.com

expectations in the clinical setting. In
the initial report describing this model,
researchers at the Washington University
School of Medicine showed the presence
of hallmarks of ALS and ascribed to
motor neuron degeneration a role in the
lethality of the model (Wegorzewska et al.,
2009). The introduction of a new model
in the ALS field was greeted with much
enthusiasm by the many researchers who
had to rely mostly on transgenic models
developed around another known ALS
mutation, namely the SOD transgenic
mice. Several labs started immediately
to use the new line for preclinical drug
testing. As it turned out, however, the
lethality characterizing the TDP-43 line
is entirely independent of motor neuron
dysfunction, let alone degeneration, but is
caused by a bowel obstruction, as showed
by researchers at The Jackson Laboratory
and collaborators at the ALS Therapy
Development Institute (Hatzipetros
et al., 2014).
Secondly, it is essential to define
clinically-relevant measures to assess

the outcome of drug treatment. If a
therapy increases survival but fails in
ameliorating the disease symptoms,
it may not be desirable for clinical
development. In this context, it is
necessary to identify the mouse model
phenotypes that correspond to specific
clinical manifestations and measure
them repeatedly during the treatment
to assess the therapeutic efficacy of the
drug candidate. For example, a good
measure of neuromuscular activity that
can be used to monitor the effectiveness
of a treatment on any disease exhibiting
motor function phenotypes is the
electrophysiological measurement of
the compound muscle action potential,
a test that has been adapted to mouse
experiments from the clinic (Bogdanik
et al., 2015).
By using the most appropriate mouse
model, designing the treatment regimen
that mirrors the clinical plan, and
combining in-life repeated measurement


Jax Labs eBook

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