Moderna Latest Study: mRNA Therapy for Treating T Cell-Mediated Autoimmune Diseases

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Moderna Latest Study: mRNA Therapy for Treating T Cell-Mediated Autoimmune Diseases

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Moderna Latest Study: mRNA Therapy for Treating T Cell-Mediated Autoimmune Diseases

Tryptophan (TRP) is an essential amino acid in the human body. Its breakdown leads to the production of active substances in the kynurenine (KYN) pathway, which plays a crucial role in regulating immune responses during cancer, pregnancy, viral infections, and autoimmune diseases.

Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme that degrades tryptophan into immunoregulatory metabolites via the kynurenine pathway. A deficiency or blockade of IDO1 can exacerbate autoimmune severity in rodent models and increase susceptibility to autoimmune diseases in humans. Despite this, therapeutic methods utilizing IDO1 for autoimmune diseases are still limited.

On September 6, 2024, Moderna, a leader in mRNA vaccines, published a research paper in Cell Reports Medicine titled “mRNA-delivery of IDO1 suppresses T cell-mediated autoimmunity.” The study demonstrates that delivering mRNA encoding IDO1 using lipid nanoparticles (LNPs) can suppress a range of T cell-mediated autoimmune diseases.

IDO1 and tryptophan 2,3-dioxygenase 2 (TDO2) are enzymes that degrade TRP into N-formylkynurenine, the rate-limiting step in the kynurenine pathway. While IDO1 and TDO2 are considered similar due to their roles in the kynurenine pathway and their exploitation by tumors, they differ significantly in structure, regulation, expression profiles, and functions. Under normal conditions, TDO2, mainly expressed in hepatocytes, degrades 80%-90% of dietary tryptophan, while IDO1 is primarily induced by interferon-γ (IFN-γ) signaling in macrophages, dendritic cells, epithelial cells, endothelial cells, and tumors.

IDO1 modulates immune responses by locally depleting tryptophan and producing immunoregulatory kynurenine. Inside cells, tryptophan depletion leads to the accumulation of uncharged tRNA, activating GCN2, which in turn reduces mTOR translation, inactivates mTOR, and inhibits the proliferation and differentiation of effector T cells. Proliferating T cells can enter the G1 phase under tryptophan-deficient conditions but will pause until tryptophan levels are restored.

Kynurenine, a ligand for the aryl hydrocarbon receptor (AhR), binds to AhR in CD4 T cells, inducing FoxP3 expression, blocking RORC, and driving CD4 T cells to differentiate into regulatory T cells (Tregs), thereby inhibiting the development of Th17 cells. Kynurenine also exerts immunoregulatory effects on CD8 T cells. In the tumor microenvironment, kynurenine binds to AhR in CD8 T cells, leading to increased PD-1 expression, which is associated with reduced effector function. Additionally, kynurenine and its downstream metabolites have been found to induce apoptosis in activated T cells.

Although genetic deletion of IDO1 does not cause spontaneous autoimmunity, IDO1 deficiency or blockade in autoimmune or inflammatory models increases the severity or incidence of disease in rodent models. Moreover, endogenous IDO1 is upregulated in successful non-human primate kidney transplants and mouse heart transplants, and blocking IDO1 leads to rejection of the transplanted organ. Conversely, overexpression of IDO1 reduces the severity of allograft rejection and autoimmune diseases in rodent models. In allografts expressing IDO1, T cell effector functions are reduced.

In humans, genetic variations in IDO1 are associated with susceptibility to autoimmune diseases such as systemic sclerosis and type 1 diabetes. While IDO1 is highly expressed in the pancreatic β cells of healthy individuals, its expression is lost in patients with autoimmune diabetes.

These observations suggest that high IDO1 expression may offer significant clinical benefits in treating autoimmune and other inflammatory diseases.

LNP-delivered mRNA has been used to produce vaccines and shows promise in treating other diseases, such as enzyme replacement therapy. In autoimmunity, LNP-delivered mRNA has been used to deliver antigens and induce immune tolerance in mouse models of experimental autoimmune encephalomyelitis (EAE) and peanut allergy. Additionally, an mRNA-delivered IL-2 mutant protein has been shown to expand endogenous Treg cells and confer protection in EAE and acute graft-versus-host disease (aGVHD).

The targeting tendency of different LNPs depends on the size and charge of the nanoparticles. Generally, most LNP formulations accumulate in the liver, independent of the mRNA cargo, making it possible to develop successful liver-specific enzyme replacement therapies. The spleen is also an important organ for LNP accumulation. Species-specific differences and inflammation also play a role in the biodistribution of protein expression from LNP-delivered mRNA.

In this latest study, the research team used LNPs to deliver mRNA encoding a human IDO1 protein variant modified with a myristoylation site from Src, anchoring the protein to the inner surface of the plasma membrane. This anchoring increased and prolonged protein expression.

The research team validated this approach in three T cell-mediated autoimmune disease models: experimental autoimmune encephalomyelitis (EAE), collagen-induced arthritis (CIA) in rats, and acute graft-versus-host disease (aGVHD). The membrane-anchored IDO1 increased protein production, leading to greater changes in kynurenine and tryptophan levels and ultimately improving disease outcomes. The therapeutic effects of IDO1 were associated with its expression in the liver and systemic tryptophan depletion.

Overall, this study demonstrates that LNP-mRNA delivery of membrane-anchored IDO1 can suppress immune responses and improve outcomes in various T cell-mediated autoimmune disease models.

Moderna Latest Study: mRNA Therapy for Treating T Cell-Mediated Autoimmune Diseases

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(source:internet, reference only)

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