NON-CODING RNAS IN AUTOIMMUNE DISORDERS: THERAPEUTIC POTENTIALS AND INTEGRATIVE NETWORK BASED COMPUTATIONAL INSIGHTS

Abstract

The recent breakthrough in the discovery of therapeutic applications of RNA have established oligonucleotide-based drugs as a promising therapeutic modality for targeting diverse diseases including the autoimmune ones- a group of complex immunological disorders resulting from a breach of tolerance. The current treatment approaches for rely on symptom management with the use of non-specific broad immunosuppressants which have their own associated adverse effects. This calls for the need of precise and target specific therapeutics. With recent progress in deciphering their molecular pathogenesis, have allowed the application of RNA based therapeutic strategies for their treatment. This thesis explores the different types of RNA therapeutics- antisense oligonucleotide (ASO), splice switching oligonucleotide (SSO), RNA interference based and aptamers, describing their mechanism of action and their applicability as therapeutic modalities, further investigating their potential for treatment of autoimmune disorders. A curated set of dysregulated microRNAs from five exemplar autoimmune diseases—rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren’s syndrome (SS), Type 1 diabetes mellitus(T1DM), and autoimmune thyroid disease (AITD)—were taken for construction of miRNA–gene interaction networks in miRNet. Network-topology metrics pinpointed a small set of high-degree “master-regulator” miRNAs that control disproportionately large gene sets across multiple diseases. Downstream KEGG pathway enrichment of the shared targets revealed a conserved signalling core—PI3K–Akt, MAPK, JAK–STAT, and the canonical Pathways in cancer module—highlighting a molecular intersection between autoimmunity and oncogenic signalling. These computational insights guide target identification which can be acted upon by the RNA therapeutics. Finally, it addresses the hurdles that limit clinical applicability and propose strategies to accelerate bench to bedside journey of RNA therapeutics in autoimmune disorders.