Developing stimuli-responsive hyperbranched poly(amidoamine) conjugates bearing Cx43, GFAP, and iSTAT3 bioligands

This grant application focuses on developing new hyperbranched poly(amido amine)s
(hPAMAMs) bioconjugates and investigation of their safety and effectiveness in treating
spinal cord injury (SCI). Our previous success with human cell replacement therapy has
inspired us to create a neuroprotective protocol to halt the progression of SCI at its early
stages. We aim to develop advanced redox responsive hPAMAMs for safe and effective
transplantation following contusive SCI to limit and minimize the detrimental effects of
rapid injury progression during the secondary phase of SCI. Our plan is to initiate
administering these hPAMAMs with disulfide bonds in their backbone 7 days after the
onset of contusive SCI, during the sub-acute phase - with their effect lasting for only 14
days. This approach will spare non-injured neuropathways and healthy tissue within the
spinal cord from the progression of the primary injury, slowing down its impact. Our
main hypotheses are: (i) reactive astrocytes are the main cellular components
responsible for both scar formation, which is a desire event, and the destructive
progression of injury (undesired) during the sub-acute phase of SCI, and (ii)
administering hPAMAM bioconjugates bearing two antibodies including Connexin43
(Cx43) and Glial Fibrillary Acidic Protein (GFAP)) and one inhibitor drug molecule
(Signal transducer and activator of transcription 3 (i-STAT3)) 7 days after contusive SCI
(with lasting effect of only 14 days), will prevent healthy neuropathways and
parenchyma from further destruction. Their neuroprotective effect, in turn, will result in
a greater number of neuropathways and a larger proportion of spinal cord parenchyma
being spared from the secondary phase of injury. Our hPAMAM-based bioconjugates
will achieve this by identifying and selectively binding to reactive-astrocytes
(temporarily) at and around the epicenter of the injury, offering a neuroprotective
approach to enhance functional recovery. The novelty of our approach lies in our ability
to produce biodegradable redox responsive hyperbranched polymers post-modified with
specific targeting functional groups, two antibodies and one inhibitor, which can safely
be used in the critical early stages of SCI. This is utmost significant because SCI is a
pathology with no current therapy and a relatively short window for treatment.