Programmable Translational-Activating RNA Therapeutic Platform Technology

SUMMARY

• Many human diseases arise from insufficient protein levels, often due to genetic mutations that result in haploinsufficiency or loss of protein function. Effectively treating these conditions necessitates therapeutic strategies capable of increasing the production of specific, vital proteins. There is a significant unmet need for programmable methods to upregulate protein expression, as the current therapeutic landscape often lacks precise and targeted approaches for restoring protein function.

• Existing gene expression modulation technologies predominantly focus on reducing protein levels through mechanisms like RNA knockdown, editing, or splicing modification. While valuable for certain conditions, these approaches do not adequately address the challenge of *increasing* protein production. Furthermore, current protein replacement therapies can be prohibitively costly, and traditional gene therapy methods often involve permanent genomic alterations, which raise significant safety and regulatory concerns. A versatile, non-genomic, and programmable method for targeted protein upregulation remains a critical gap in therapeutic options.

The Proposed Solution:

• The faculty inventor developed a bifunctional RNA molecule that combines a programmable guide RNA with a viral internal ribosome entry site (IRES) to enhance target mRNA translation. The guide RNA specifically binds to a target transcript, positioning the IRES nearby to recruit ribosomes and significantly increase protein synthesis. Various viral IRES elements are employed to optimize ribosome recruitment and translation initiation without needing additional machinery. Validated in cell-based assays, this RNA-based translational activator effectively upregulates protein expression, offering a programmable method for addressing protein deficiency.

   

FIGURE

A)  taRNA is a bifunctional “molecular glue” that binds an mRNA of interest and recruits translational activation machinery to the mRNA. taRNAs are most effective when bound to the 3’ UTR.
B)  The inventors’ custom taRNA (gRNA-IRES). IRES RNAs perform their recruiting function. Adding a guide-RNA on an IRES causes the IRES-captured ribosomes to accumulate near targeted mRNA and then accelerate translation. The gRNA-IRES single RNA molecule boosts specific protein levels.

ADVANTAGES

ADVANTAGES

• taRNAs are small (100-200 nucleotides) which enables robust delivery, at the RNA or viral level

• As gene activation by taRNAs depends on cell-specific transcriptomes, they enable highly-individualized dosing

• Enables programmable and targeted upregulation of specific proteins

• Addresses diseases caused by protein deficiency or haploinsufficiency.

APPLICATIONS

• Oncology
• Rare disease
• Haploinsufficiency diseases
• Neurodegenerative disease therapy
• Therapeutic protein production

PUBLICATIONS

• Cao, Y., Liu, H., Lu, S.S. et al. RNA-based translation activators for targeted gene upregulation. Nat Commun 14, 6827 (2023)

February 9, 2022

Proof of concept

Patent Pending

Licensing,Co-development

Bryan Dickinson