Synthetic cellular signaling pathways and uses thereof
Inventors
Grinstaff, Mark W. • Kirsch, Jack R. • Williamson, Amanda K. • Tingley, Brett
Assignees
Publication Number
US-12239718-B2
Publication Date
2025-03-04
Expiration Date
2043-07-12
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Abstract
The disclosure relates generally to methods and compositions for generation or enhancement of partial or complete cellular signaling pathways.
Core Innovation
The invention describes methods and compositions for simultaneously generating or enhancing partial or complete cellular signaling pathways via exogenously delivered polynucleotides, specifically messenger RNAs (mRNAs). This is achieved by incorporating both a ligand and its corresponding target (either its cognate receptor or an inhibitor of a suppressor) into one or more linked nucleic acid molecules. The nucleic acids can be designed such that the production of the ligand and the target molecule occurs via cap-dependent or cap-independent translation mechanisms, and both components may be expressed from the same polycistronic nucleic acid.
Traditional therapies often rely on the presence and accessible density of endogenous targets for efficacy, which can be limited in disease states where receptors are downregulated or ligand bioavailability is altered. The problem addressed is that such dysregulation leads to ineffectiveness of therapeutics based on endogenous ligands or drugs acting through specific signaling pathways, especially in diseases where the expression of the necessary targets is insufficient or suppressed.
By delivering both the ligand and its receptor or modulator as mRNA, the invention overcomes the challenge of variable or insufficient target density. This allows for the restoration or activation of signaling cascades independent of disease state, cell type, or endogenous protein expression profiles. The technology encompasses nucleic acid constructs, compositions, vectors, cellular systems, and lipid particle-based delivery formulations, enabling the in situ translation and activation of therapeutic pathways for amplification of desired biological effects.
The invention is demonstrated for various therapeutic settings, including simultaneous expression of both a ligand and its cognate receptor or an inhibitor of a ligand suppressor, with particular examples given for relaxin-RXFP1, IL-10-IL-10Rα, and IGF-1-PAPPA2 circuits, each designed to overcome pathway deficiencies inherent to disease states such as fibrotic, cardiovascular, immunological, oncological, and degenerative diseases.
Claims Coverage
There are five independent claims, each representing a core inventive feature covering nucleic acid combinations, compositions, and lipid particles with specified structural, functional, and compositional components.
Nucleic acid combination encoding ligand and target with differential translation mechanisms
A nucleic acid combination comprising a first nucleic acid molecule encoding a ligand and a second nucleic acid molecule encoding a target molecule (where the target is a cognate receptor of the ligand or an inhibitor of a suppressor of the ligand). One of the ligand and target molecule is translated via a cap-dependent manner and the other via a cap-independent manner, with both nucleic acids covalently linked to form a nucleic acid encoding both components. The ligand is defined as a protein, protein fragment, or fusion protein, and the target is a protein or polypeptide.
Composition comprising the nucleic acid combination
A composition comprising the aforementioned nucleic acid combination, encompassing the structural features and translation mechanisms described above.
Lipid particle comprising the nucleic acid combination and an ionizable lipid
A lipid particle comprising the nucleic acid combination (as described) and an ionizable lipid, where the lipid particle can be formulated as a nanoparticle and may further comprise a non-cationic lipid, a conjugated lipid that inhibits aggregation of particles, or a sterol. The particle may include: an ionizable lipid (20–90 mol%), a non-cationic lipid (5–30 mol%), a conjugated lipid that inhibits aggregation (0.5–20 mol%), and a sterol (20–50 mol%).
The independent claims provide broad coverage for systems and delivery vehicles enabling the simultaneous in situ production of ligands and their targets, via linked nucleic acids with distinct translational control, and encompassing pharmaceutical compositions and advanced lipid-based delivery particles with defined structural and compositional characteristics.
Stated Advantages
The technology enables amplification and therapeutic activity of signaling pathways irrespective of cell type or disease state, overcoming limitations due to variable or suppressed target expression.
It increases efficacy of ligand-based therapies without requiring increased dosage of the ligand.
The platform allows for simultaneous restoration and activation of endogenous signaling cascades, addressing the failures of therapies caused by disease-related signaling pathway dysregulation.
Compositions based on mRNA are temporally limited and avoid the risk of genomic integration, supporting a strong safety profile for therapeutic applications.
The approach supports cell-type and disease-state independent activation of therapeutic pathways, broadening the applicability of ligand-based treatments across various indications.
Documented Applications
Treatment of fibrotic diseases such as arthrofibrosis, systemic sclerosis, hypertrophic or keloid scars, interstitial pulmonary disease, and hepatic fibrosis.
Therapeutic intervention for cardiovascular diseases, heart failure, and acute heart failure.
Treatment of immunological and autoimmune disorders including rheumatoid arthritis and conditions with immune activation-induced suppression of receptor expression.
Therapy for degenerative diseases such as osteoarthritis, including restoration of IGF-1/IGF-1R signaling and enhancement of chondrocyte function.
Applications in neuromuscular and developmental disorders like Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, spinal muscular atrophy, cerebral palsy, traumatic brain injury, arthrogryposis multiplex congenita, and contractures.
Administration via various routes, including intra-articular, intramuscular, subcutaneous, intradermal, intravenous, inhalation (as aerosol), mucosal, topical (cream, gel, microneedle), and oral delivery forms.
Use in restoration and potentiation of biological signaling in tissues where endogenous receptor or ligand expression is compromised or suppressed due to disease.
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