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Immunoregulatory effect of microparticle delivered STING agonist in the control of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS)

Award Number: R21AI154772
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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While multiple antiinflammatory therapies are effective in suppressing relapsing-remitting multiple sclerosis (RRMS) disease progression, they have significant side effects and toxicity. We are still seeking a disease specific treatment that would provide an antigen-specific immune tolerance reconstitution. We used microparticle (MP)-encapsulated STING agonist cGAMP to increase its delivery into phagocytic antigen presenting cells (APCs), particularly dendritic cells (DCs). A novel acid-sensitive polymer, acetalated dextran (Ace-DEX) allows regulated MP breakdown due to its pH sensitivity in intracellular acidic compartments. Our preliminary data have demonstrated that the intracellular delivery of MPs encapsulating 2’3’cyclic GMP-AMP dinucleotide (cGAMP) suppressed experimental autoimmune encephalomyelitis (EAE), an animal model of MS, when administered before and at the peak of clinical disease. The therapeutic effect of cGAMP MPs in RR and chronic EAE was mediated via STING-induced IL-27 and IL-10 production, since the therapeutic effect was abrogated in IL-27ra-/- and IL-10-/- mice, while partial disease suppression was maintained in Ifnar-/- mice. Our central hypothesis is that intracellular cGAMP MP delivery will induce IL-27 and IL-10-producing tolerogenic DCs that regulate the differentiation and expansion of IL-10-producing iTregs. We will characterize cGAMP MP tolerogenic DC phenotype and function, as well as suppressive capacity of the induced regulatory CD4+IL-10+ cells, in particular their expression of FoxP3 and type 1 iTreg (Tr1) markers. We propose that presentation of MHC class II DR2-anchored peptide mixtures (DR2-APMs) by cGAMP MP-induced tolerogenic DCs from DR2+ patients with relapsing remitting multiple sclerosis (RRMS) may reconstitute antigen-specific immune tolerance. In order to identify the mechanisms of cAMP MP-mediated disease suppression, we will pursue following specific aims: 1) Demonstrate that cGAMP MP treatment induces iTreg cell expansion in EAE. The proposed studies will determine to what extent cGAMP MP treatment of EAE induces the expansion of CD4+CD25+IL-27R+IL-10+ Tregs in the peripheral immune organs and the CNS inflammatory infiltrates. Studies using aCD25mAb will confirm the role of iTregs in the therapeutic effect. The role of FoxP3+Tregs will be examined using transient inducible FoxP3+Treg depletion and mice with selective FoxP3+Treg IL-27R depletion. 2) In human in-vitro studies, we will characterize cGAMP MP-induced tolerogenic DCs and their capacity to induce iTregs in RRMS patients. Specific experiments will determine the capacity of cGAMP MP-treated monocytes and DCs to induce iTreg expansion, determine the transcriptome of cGAMP MP IL-27- and IL-10- induced Tregs and the reconstitution of their suppressive capacity. Finally, co-administration of cGAMP MPs with DR2-APMs to DCs from RRMS patients will test their capacity to induce antigen-specific tolerogenic DCs and Tregs. The study will provide preclinical data required to translate this therapeutic approach into clinical use in patients with RRMS


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2022 ( Subtotal = $195,966 )
2022	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	2	3/10/2022	NON-COMPETING CONTINUATION	$195,966
														Subtotal = $195,966

Issue Date FY: 2021 ( Subtotal = $234,966 )
2021	2021	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	1	4/14/2021	NEW	$234,966
														Subtotal = $234,966

Grand Total All Awards = $430,932

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Immunoregulatory effect of microparticle delivered STING agonist in the control of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS)

Award Number: R21AI154772

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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