Autoregulated MBNL Gene Therapy for Myotonic Dystrophy

Next-Generation Gene Therapy Vectors with Tunable, Tissue-Specific, and Auto-Regulated Expression for Superior Safety and Efficacy

This technology introduces recombinant adeno-associated virus (rAAV) vectors engineered to enable precise, regulated expression of therapeutic genes. Recombinant viruses can deliver therapeutic gene expression constructs to patients as a form of genetic therapy. Patients suffering from a disease or condition associated with a particular genetic mutation can be treated with a recombinant virus that delivers a therapeutic gene construct to the patient to supplement or replace the function of the mutated gene.

Myotonic dystrophy (DM) types 1 and 2 are caused by expanded CTG repeats in the DMPK gene and CCTG repeats in the CNBP gene, respectively. Both diseases are highly multi-systemic with symptoms in skeletal muscles, cardiac tissue, gastrointestinal tract, endocrine system, and central nervous system. Myotonic dystrophy 1 can also manifest in a severe form, known as congenital DM1, causing profound developmental delays. The condition has a 25% chance of death before 18 months and a 50% chance of survival into the mid-30s. The CTG/CCTG repeats in DM1 and DM2 are transcribed into RNA and sequester members of the Muscleblind-like (MBNL) family of RNA-binding proteins. Traditional gene therapy using viral vectors is limited by payload size and imprecise control of therapeutic gene expression, often resulting in suboptimal outcomes or side effects. By incorporating introns and regulatory elements responsive to intracellular factors, these vectors deliver more physiologically relevant gene expression—overcoming the limitations of conventional “minigene” approaches and enhancing both safety and therapeutic benefit.

Researchers at the University of Florida have developed a gene therapy platform that leverages Muscleblind-like dependent recombinant adeno-associated virus (rAAV) vectors for highly regulated delivery of therapeutic genes. By engineering these vectors to include specialized introns and regulatory elements responsive to intracellular factors, it enables precise, tissue-specific, and auto-regulated gene expression. This innovation addresses longstanding challenges in gene therapy—such as payload limitations and lack of expression control—offering a safer, more effective solution for treating a wide range of genetic disorders.

Application

Treats genetic diseases requiring precise control of therapeutic gene expression with autoregulated MBLN gene therapies

Advantages

• Precise Regulation: Enables fine-tuned, auto-regulated, or tissue-specific expression of therapeutic genes
• Expanded Design Flexibility: Supports inclusion of introns and regulatory sequences, not just coding regions
• Improved Safety: Reduces risk of overexpression-related toxicity by matching physiological gene regulation
• Broad Disease Applicability: Compatible with a wide range of target genes and regulatory proteins
• Customizable Control: Expression can be modulated by endogenous or engineered intracellular factors

Technology

This platform leverages recombinant AAV vectors carrying engineered genomes that include:

• One or more introns whose splicing is regulated by specific intracellular factors (proteins, RNAs, or protein-RNA complexes)
• Binding sites for tissue-specific or condition-specific RNA binding proteins (e.g., MBNL, SR, hnRNP, RbFox, CELF, Nova, PTB families)
• Optional inclusion of regulatory exons, RNAi elements, or truncated/naturally derived intronic and exonic sequences to further refine expression
• Modularity to encode both therapeutic genes and their regulatory factors within the same vector, enabling autoregulation or feedback control

By harnessing the cell’s own splicing machinery and regulatory proteins, these vectors achieve expression profiles closely mimicking natural gene regulation—enabling safer, more effective, and more predictable gene therapies.