Locanabio, a genetic medicines company dedicated to developing RNA-targeted therapeutics for patients with rare genetic neuromuscular and neurodegenerative diseases, has unveiled groundbreaking data showcasing the successful packaging and delivery of its proprietary small nuclear RNA (snRNA) platform using adeno-associated virus (AAV).
The presented findings highlight the platform’s applications, which have demonstrated robust, dose-dependent exon skipping at multiple exons, potentially enabling the restoration of nearly full-length dystrophin protein—a crucial development in the treatment of Duchenne muscular dystrophy (DMD) with a single administration therapy.
John Leonard, Ph.D., Chief Scientific Officer of Locanabio, emphasized the significance of this achievement: “Our vectorized snRNA platform combines the therapeutic potential of exon skipping with the delivery advantages of an AAV gene therapy. Exon skipping enables the production of a near full-length dystrophin from the native transcript expressed in affected tissues.
However, prior exon skipping approaches with first-generation antisense oligonucleotides (ASOs) have been limited by poor biodistribution and tolerability, resulting in negligible restoration of dystrophin protein.
We have developed a packaging and manufacturing solution that enables us to efficiently package multiple snRNAs into a single AAV vector to enhance exon skipping potency and enable relevant tissue distribution and potentially durable effect following a single administration.”
The study demonstrated dose-dependent exon skipping and dystrophin restoration using snRNA constructs targeting exons 51, 53, 44, or 45 in human DMD cells with relevant mutations.
Locanabio’s lead candidate, LBIO-115—an AAV expressing multiple snRNAs promoting exon 51 skipping—was evaluated in a humanized mouse model of DMD, with intravenous administration resulting in dose-dependent exon skipping and increased dystrophin protein expression, indicating functional restoration of dystrophin. A similar therapeutic profile was observed for LBIO-135, targeting exon 53, in a mouse model also amenable to exon 53 skipping.
Jim Burns, Ph.D., Chief Executive Officer of Locanabio, celebrated the transformative potential of their vectorized snRNA platform: “These proof-of-concept data demonstrate the potential of our proprietary vectorized snRNA platform to overcome previous challenges with packaging multiple snRNA constructs into the AAV genome and open up this field for therapeutic application.
Eighty percent of DMD mutations are amenable to exon skipping, and therapies that target skipping of exons 51, 53, 44, and 45 could potentially address 35% of the total DMD patient population.” Locanabio anticipates submitting an investigational new drug (IND) application for LBIO-115 in mid-2024, marking a significant step toward addressing the unmet needs of DMD patients.
Locanabio’s Vectorized snRNA Platform
Locanabio is revolutionizing the field of genetic medicine by harnessing the power of engineered small nuclear RNAs (snRNAs) delivered through adeno-associated virus (AAV) gene therapy in a one-time administration.
These snRNAs offer a cutting-edge approach to precisely target disease-causing RNA with unparalleled precision and effectiveness. Importantly, snRNAs are non-immunogenic, making them an ideal candidate for therapeutic interventions.
The versatility of snRNAs is remarkable, as they can address a wide range of mechanisms underlying genetic diseases. This includes the ability to facilitate exon-skipping, which can either restore a proper reading frame in disrupted genes or regulate mRNA and protein expression to rectify disease-related imbalances.
Moreover, snRNAs can be programmed to target specific toxic RNA repeat sequences implicated in various disorders. Additionally, they have the unique capability to recruit endogenous adenosine deaminases acting on RNA (ADARs) for therapeutic RNA editing, allowing for precise and customized RNA modifications to correct disease-causing mutations.
One of the key advantages of snRNAs is their small size, which allows for the delivery of multiple snRNAs within a single AAV vector. This innovative approach not only enhances therapeutic potency but also facilitates the simultaneous targeting of multiple RNA-based disease drivers.
Locanabio’s pioneering work with snRNAs and AAV gene therapy represents a promising frontier in the treatment of rare genetic neuromuscular and neurodegenerative diseases. Their approach holds the potential to provide lasting and transformative benefits to patients, offering hope for previously untreatable conditions.
About Duchenne Muscular Dystrophy (DMD)
Duchenne muscular dystrophy (DMD) is an extremely rare and devastating X-linked recessive degenerative neuromuscular disorder. It is primarily caused by mutations in the dystrophin gene, which is notable for being the largest gene in the human genome.
These genetic mutations can occur at various points within the dystrophin gene, most commonly resulting in large exon deletions or duplications. These mutations lead to the production of dysfunctional dystrophin protein.
Dystrophin is a critical protein in muscle function, serving a pivotal structural role in muscle fibers. It forms part of a group of proteins whose primary function is to fortify muscle fibers, safeguarding them against injury as muscles undergo the contraction and relaxation processes. Without properly functioning dystrophin, muscle cells are vulnerable to damage, initiating a cycle of muscle wasting.
Individuals affected by DMD experience a relentless progression of symptoms, including progressive muscle wasting, difficulty in controlling movement, respiratory failure, and heart failure.
These debilitating effects typically result in the need for full-time wheelchair use during the teenage years and early twenties. Tragically, DMD significantly reduces life expectancy, making it a formidable challenge for affected individuals and their families.
Given its rarity and severity, DMD represents a poignant example of the importance of innovative medical research and therapies, such as those being developed by companies like Locanabio, to address the unmet needs of individuals living with this devastating condition.