Biomedical Engineering Reference
In-Depth Information
7.8
Applications: Using Lipidoids to Treat
Disease Models
One of the most noteworthy advantages to RNAi therapeutics is that
effective delivery does not depend on RNA sequence. Consequently,
the same delivery vehicle can be leveraged to treat many diseases.
The best demonstration of this is the effective application of 98N
-5
to three dissimilar diseases: hypercholesterolemia, malaria, and
metastatic prostate cancer. Both hypercholesterolemia and malaria
are impacted by hepatocytes, but in disparate ways. Hepatocytes
produce and remove cholesterol from the bloodstream, making
them critical in cholesterol homeostasis. Malaria, on the other hand,
is a multi-stage disease in which small parasites, termed sporozites,
mature in the liver before rapidly infecting red blood cells.
12
-5 reduced hypercholesterolemia by silencing PCKS9, a
gene whose product binds and degrades low-density lipoprotein
receptors (LDLRs ) in the liver.
98N
12
27
LDLRs reduce serum concentrations
of this “bad” cholesterol by removing it from the bloodstream. This
mechanism, which has been confirmed in mice and humans, is made
pathological by somatic or familial mutations that lead to PCKS9
overexpression.
28, 29
Importantly, anti-PCKS9 therapeutics, while
successful in many patients, were unable to sufficiently reduce
cholesterol levels in others.
The combination of a well-defined
pathway, a pathology dependent on a gain-of-function mutation, and
a patient population unresponsive to traditional therapeutics made
PCKS9 an excellent candidate for an RNAi therapy. As a result, we
investigated the effect of silencing PCKS9 in normal mice, transgenic
mice, rats, and non-human primates.
27
The use of multiple animal
models was critical, since rodents transport most of their cholesterol
as high-density lipoproteins (HDL), whereas primates transport
the majority of the cholesterol as LDL. Such investigations further
illustrate the importance of understanding how different species
might respond to new therapies.
27
30
In addition to testing multiple animal models, it is important to
confirm that therapeutic responses are due to RNAi rather than off-
target or immunostimulatory effects.31
31
Although there is no formal
standard procedure to demonstrate this, the case for an on-target
RNAi-mediated effect is strengthened by (a) modifying siRNA with
non-immunostimulatory 2
-O-methyl groups, (b) testing siRNA for
cytokine induction in whole blood or
′
in vivo
, (c) using a scrambled
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