Large- and Small-Animal Studies of Safety, Pharmacokinetics, and Biodistribution of Inflammasome-Targeting Nanoligomer in the Brain and Other Target Organs

Immune malfunction or misrecognition of healthy cells
and tissue,
termed autoimmune disease, is implicated in more than 80 disease conditions
and multiple other secondary pathologies. While pan-immunosuppressive
therapies like steroids can offer limited relief for systemic inflammation
for some organs, many patients never achieve remission, and such drugs
do not cross the blood–brain barrier, making them ineffective
for tackling neuroinflammation. Especially in the brain, unintended
activation of microglia and astrocytes is hypothesized to be directly
or indirectly responsible for multiple sclerosis, amyotrophic lateral
sclerosis, Parkinson’s disease, and Alzheimer’s disease.
Recent studies have also shown that targeting inflammasomes and specific
immune targets can be beneficial for these diseases. Furthermore,
our previous studies have shown targeting NF-κB and NLRP3 through
brain penetrant Nanoligomer cocktail SB_NI_112 (abbreviated as NI112)
can be therapeutic for several neurodegenerative diseases. Here, we
show safety-toxicity studies, followed by pharmacokinetics and biodistribution
in small- (mice) and large-animal (dog) studies of this inflammasome-targeting
Nanoligomer cocktail NI112. We conducted studies using four different
routes of administration: intravenous, subcutaneous, intraperitoneal,
and intranasal, and identified the drug concentration over time using
inductively coupled plasma mass spectrometry in the blood serum, the
brain (including different brain regions), and other target organs
such as liver, kidney, and colon. Our results indicate that the Nanoligomer
cocktail has a strong safety profile and shows high biodistribution
(F ∼ 0.98) and delivery across multiple routes
of administration. Further analysis showed high brain bioavailability
with a ratio of NI112 in brain tissue to blood serum of ∼30%.
Our model accurately shows dose scaling, translation between different
routes of administration, and interspecies scaling. These results
provide an excellent platform for human clinical translation and prediction
of therapeutic dosage between different routes of administration.