Anti-Transferrin Receptor PMO Conjugates for DMD Exon 44 Skipping
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Solution Overview
Problem
Current therapies for Duchenne Muscular Dystrophy (DMD) do not effectively address exon 44 skipping, which affects approximately 6% of the patient population, despite extensive research, leaving a significant unmet need for treatment options.
Innovation Solution
Development of phosphorodiamidate morpholino oligonucleotide (PMO) conjugates comprising an anti-transferrin receptor antibody or its antigen binding fragment, conjugated to a PMO molecule that hybridizes to the exon 44 acceptor splice site in the DMD gene, inducing exon 44 skipping to generate a truncated dystrophin protein.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antisense oligonucleotides are used for exon skipping, then they can induce exon skipping in target tissue, but they lack sufficient tissue specificity and delivery efficiency to muscle cells
Solution Approach 1:
The patent uses an antibody as an intermediary carrier to deliver the antisense oligonucleotide to the target tissue. The antibody-oligonucleotide conjugate allows the oligonucleotide to be transported specifically to muscle cells expressing the target antigen, resolving the contradiction between achieving exon skipping efficacy and obtaining tissue specificity.
Solution Approach 2:
The patent combines the antibody (for targeted delivery) and the antisense oligonucleotide (for exon skipping function) into a single conjugate molecule. This merging allows the therapeutic agent to simultaneously achieve both specific tissue targeting and effective exon skipping in the same molecular entity.
2Productivity
If naked antisense oligonucleotides are administered, then they can potentially reach target cells, but they suffer from poor cellular uptake and rapid clearance
Solution Approach 1:
The patent changes the physical and chemical parameters of the oligonucleotide by conjugating it to an antibody. This modification alters the molecule's size, charge, and recognition properties, thereby improving its cellular uptake efficiency and extending its circulation half-life through the antibody's protective effect and targeted delivery mechanism.
3Quantity of substance
If non-specific oligonucleotide delivery is used, then broad distribution occurs, but off-target effects and reduced therapeutic index result
Solution Approach 1:
The antibody serves as a selective intermediary that directs the oligonucleotide specifically to target muscle cells expressing the desired antigen. This targeted delivery reduces off-target distribution to non-muscle tissues, thereby minimizing off-target effects while maintaining adequate therapeutic substance levels in the intended tissue.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The PMO conjugates effectively induce exon 44 skipping in muscle cells, leading to the production of a functional truncated dystrophin protein, potentially treating DMD by restoring muscle function.
Implementation Method 1
the PMO molecule hybridizes to the exon 44 acceptor splice site in a pre-mRNA transcript of the DMD gene
Data Source
AI summary
Disclosed herein are antibody oligonucleotide conjugates and pharmaceutical compositions that induce an alteration in an incorrectly spliced dystrophin mRNA transcript to induce exon 44 skipping. Also described herein include methods for treating muscle dystrophy including Duchenne muscular dystrophy that comprises administering antibody oligonucleotide conjugates or a pharmaceutical composition that induces alteration in an incorrectly spliced dystrophin mRNA transcript to induce exon 44 skipping.