SAN DIEGO, Oct. 06, 2023 (GLOBE NEWSWIRE) -- Locanabio, Inc., a genetic medicines company developing RNA-targeted therapeutics for patients with rare genetic neuromuscular and neurodegenerative diseases, today announced the presentation of data demonstrating the packaging and delivery of its proprietary small nuclear RNA (snRNA) platform using adeno-associated virus (AAV). The poster describes specific applications of this vectorized platform showing robust dose-dependent exon skipping at multiple exons enabling restoration of nearly full-length dystrophin protein for the potential treatment of DMD in a single administration therapy.
“As these data demonstrate, our vectorized snRNA platform combines the therapeutic potential of exon skipping with the delivery advantages of an AAV gene therapy,” said John Leonard, Ph.D., Locanabio’s chief scientific officer. “Gene therapy approaches to DMD are limited by the large size of the dystrophin protein necessitating the use of a replacement gene encoding a microdystrophin that lacks important functional domains of the full-length protein. In contrast, 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.”
In human DMD cells harboring relevant mutations, dose-dependent exon skipping and dystrophin restoration was demonstrated with snRNA constructs specific for exons 51, 53, 44, or 45. Locanabio’s lead candidate, LBIO-115, an AAV expressing multiple snRNAs that specifically promote skipping of exon 51, was evaluated in a humanized mouse model of DMD (del52hDMD.mdx mice) amenable to exon 51 skipping. Intravenous administration resulted in dose-dependent exon skipping that correlated with tissue expression of the snRNA and that was sustained throughout the 12-week study. Importantly, dystrophin protein expression increased between weeks 4 and 12 and resulted in relocalization of nNOS expression to the sarcolemma, indicating restoration of a functional dystrophin protein following exon skipping. A similar therapeutic profile was observed for LBIO-135, an AAV expressing multiple snRNAs designed to promote skipping of exon 53, in the del52hDMD/mdx mouse model which is also amenable to exon 53 skipping. Locanabio’s presentation at WMS2023 is available on the Scientific Posters and Publications page of the company’s website.
“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,” said Jim Burns, Ph.D. Locanabio’s chief executive officer. “The ability to package multiple snRNA cassettes amplifies potency relative to delivery of single ASOs for exon skipping. Our first product candidate, LBIO-115, is advancing through preclinical studies and we expect to submit an investigational new drug (IND) application in mid-2024. 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’s Vectorized snRNA Platform
Locanabio is using engineered small nuclear RNAs, or snRNAs, delivered using AAV gene therapy to target disease-causing RNA with a one-time administration. snRNAs target RNA exclusively and precisely and are non-immunogenic. They can effect a wide variety of mechanisms including exon-skipping to either restore a reading frame or regulate mRNA and protein expression, target disease causing toxic RNA repeat sequences and recruit endogenous adenosine deaminases acting on RNA (ADARs) for therapeutic RNA editing. Their small size allows the delivery of multiple snRNAs in a single AAV vector which can be used to increase potency or allow targeting of multiple RNAs.
About Duchenne Muscular Dystrophy (DMD)
DMD is a rare fatal X-linked recessive degenerative neuromuscular disorder caused by mutations in the dystrophin gene. The disease affects approximately 1 in every 3,500 to 5,000 males born worldwide.
The dystrophin gene is the largest human gene. DMD causing mutations can occur at various places in the gene and most result in large exon deletions or duplications and dysfunctional dystrophin protein. Dystrophin plays a key structural role in muscle. It is one of a group of proteins whose function is to strengthen muscle fibers and protect them from injury as muscles contract and relax. Without it, muscle cells become damaged which leads to muscle wasting. Patients with DMD experience progressive muscle wasting, difficulty controlling movement, respiratory failure and heart failure leading to full time wheelchair use in teens and early 20’s and reduced life expectancy.
About Locanabio, Inc.
Locanabio is a leader in developing a new class of genetic medicines that has the potential to significantly improve the lives of patients with devastating genetic diseases by correcting the message of disease-causing RNA. Our proprietary platform uses gene therapy to deliver RNA-binding systems, including snRNA, Cas13d and PUF, that can be engineered to selectively manipulate disease-causing RNA by multiple mechanisms. Our systems are designed to provide a durable therapy with a single administration without altering a cell’s DNA. Locanabio’s platform has applications across a range of tissues and diseases, and we are currently advancing programs in rare genetic neuromuscular and neurodegenerative diseases. For more information, visit www.locanabio.com.
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Wheelhouse LSA
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