Targeted-Neuroinflammation
Mitigation Using Inflammasome-Inhibiting
Nanoligomers is Therapeutic in an Experimental Autoimmune Encephalomyelitis
Mouse Model
posted on 2024-03-25, 14:04authored bySadhana Sharma, Sydney Risen, Vincenzo S. Gilberto, Sean Boland, Anushree Chatterjee, Julie A. Moreno, Prashant Nagpal
Multiple sclerosis (MS) is a debilitating autoimmune
disease that
impacts millions of patients worldwide, disproportionately impacting
women (4:1), and often presenting at highly productive stages of life.
This disease affects the spinal cord and brain and is characterized
by severe neuroinflammation, demyelination, and subsequent neuronal
damage, resulting in symptoms like loss of mobility. While untargeted
and pan-immunosuppressive therapies have proven to be disease-modifying
and manage (or prolong the time between) symptoms in many patients,
a significant fraction are unable to achieve remission. Recent work
has suggested that targeted neuroinflammation mitigation through selective
inflammasome inhibition can offer relief to patients while preserving
key components of immune function. Here, we show a screening of potential
therapeutic targets using inflammasome-inhibiting Nanoligomers (NF-κB1,
TNFR1, TNF-α, IL-6) that meet or far-exceed commercially available
small-molecule counterparts like ruxolitinib, MCC950, and deucravacitinib.
Using the human brain organoid model, top Nanoligomer combinations
(NF-κB1 + TNFR1: NI111, and NF-κB1 + NLRP3: NI112) were
shown to significantly reduce neuroinflammation without any observable
negative impact on organoid function. Further testing of these top
Nanoligomer combinations in an aggressive experimental autoimmune
encephalomyelitis (EAE) mouse model for MS using intraperitoneal (IP)
injections showed that NF-κB1 and NLRP3 targeting Nanoligomer
combination NI112 rescues mice without observable loss of mobility
or disability, minimal inflammation in brain and spinal cord histology,
and minimal to no immune cell infiltration of the spinal cord and
no demyelination, similar to or at par with mice that received no
EAE injections (negative control). Mice receiving NI111 (NF-κB1
+ TNFR1) also showed reduced neuroinflammation compared to saline
(sham)-treated EAE mice and at par/similar to other inflammasome-inhibiting
small molecule treatments, although it was significantly higher than
NI112 leading to subsequent worsening clinical outcomes. Furthermore,
treatment with an oral formulation of NI112 at lower doses showed
a significant reduction in EAE severity, albeit with higher variance
owing to administration and formulation/fill-and-finish variability.
Overall, these results point to the potential of further development
and testing of these inflammasome-targeting Nanoliogmers as an effective
neuroinflammation treatment for multiple neurodegenerative diseases
and potentially benefit several patients suffering from such debilitating
autoimmune diseases like MS.