In the last 25 years, the genes responsible for 50% of the 7,000 rare monogenic diseases have been identified. These diseases, numbering between 5,000 and 8,000, affect a significant portion of the global population. Advances in genomic technologies have facilitated the identification of genes involved in monogenic diseases, which are caused by mutations in a single gene with different inheritance patterns. This has improved our understanding of pathogenic mechanisms such as haploinsufficiency, where insufficient protein production leads to disease.

Despite these advances, only 5% of rare diseases have available treatments. There is a significant gap between gene identification and the development of effective therapies, mainly due to the lack of focus on translational research for these diseases. Creative strategies, such as low-cost and low-risk research programs, are needed. Most genetic disorders can be considered dysregulations of gene dosage, suggesting the possibility of therapies based on DNA or protein replacement, or increasing their levels.

An innovative solution lies in small activating RNAs (saRNAs), 21-nucleotide molecules capable of activating endogenous genes by binding to specific promoters and recruiting the transcriptional machinery. Our team has developed the saRNA T1000, which effectively activates key genes involved in the formation of myeloid cells in diseases such as dyskeratosis congenita (DC) and congenital neutropenias (CN). Now, we aim to expand this technology to address other rare diseases (RDs) such as DDX3X Syndrome.

Our approach includes designing saRNAs to activate wild-type alleles or compensatory genes, restoring protein functionality. Additionally, we will explore the use of RNA to induce the activation of redundant genes, offering new therapeutic possibilities. This project will also develop a bioinformatics workflow to facilitate the design and application of saRNAs for other diseases, maximizing efficiency in therapy development.

The potential of saRNAs has already been validated in clinical trials for liver cancer, reinforcing their viability for addressing rare diseases. This project not only focuses on specific conditions, promoting precision medicine, but also proposes a generalizable platform for designing RNAbased therapies, transforming the treatment of multiple rare diseases and improving patients' quality of life.