LBIO-115 demonstrates robust exon 51 skipping resulting in high levels of dystrophin restoration in patient-derived muscle cells and an in vivo DMD disease model

Cas13d Multi-targeting efficiently knocks down both sense and antisense toxic RNAs and decreases dipeptide repeats in C9orf72 ALS patient fibroblasts and an in vivo disease model

SAN DIEGO, CA, USA I May 16, 2023 I Locanabio, Inc., a genetic medicines company developing RNA-targeted therapeutics for patients with rare genetic neuromuscular and neurodegenerative diseases, announced the presentation of data from its lead vectorized snRNA exon skipping program, LBIO-115, in development for the treatment of Duchenne muscular dystrophy (DMD). A second presentation highlights data from the company’s Cas13d multi-targeting program for C9orf72-related amyotrophic lateral sclerosis (ALS). The ASGCT 26th Annual Meeting is being held May 16-20, in Los Angeles.

“The preclinical data presented at the ASGCT meeting highlight Locanabio’s expertise in therapeutic RNA modification with two different payloads from our versatile drug development platform: our proprietary vectorized snRNAs and Cas13d which are designed to durably address disease causing RNA using different mechanisms,” said Jim Burns, Ph.D., Locanabio’s chief executive officer. “In both programs, we have generated important proof of concept data in both human cell and in vivo disease models that support further development of these product candidates.”

The first presentation titled Small Nuclear RNA-mediated Exon51 Skipping AAV9 Gene Therapy for the Treatment of Duchenne Muscular Dystrophy describes studies using LBIO-115, an AAV9 vector generated using Locanabio’s proprietary packaging methodology to deliver multiple snRNAs to induce exon 51 skipping. The poster describes data that demonstrate high levels (>90%) of exon 51 skipping and dystrophin restoration in human DMD skeletal and cardiac muscle cells after LBIO-115 treatment. In a relevant in vivo model (del52hDMD/mdx), robust levels of exon 51 skipping were observed at four weeks post-intramuscular administration of LBIO-115. Dose-dependent exon 51 skipping and dystrophin protein restoration was also seen in heart muscle, diaphragm and gastrocnemius at three and four weeks after intravenous administration. In these studies, LBIO-115 was well tolerated and resulted in minimal off-target activity. Data were also presented demonstrating the ability to rapidly screen snRNA target sequences for other therapeutically relevant exons to advance additional snRNA product candidates for DMD.

Dr. Burns added, “Existing early clinical studies in DMD patients with a duplication in exon 2 provided clinical validation for an snRNA-mediated exon skipping approach. Locanabio has developed a proprietary AAV packaging and manufacturing solution to improve manufacturability and product homogeneity, which we believe will unlock the potential of snRNAs for a broad range of therapeutic applications. We are excited about the potential of LBIO-115, which is currently in IND-enabling studies, because of the robust exon 51 skipping we have observed. We intend to use a bespoke strategy to expand our pipeline, leveraging the same snRNA backbone design while switching out the snRNA targeting sequences for additional exons, potentially accelerating the development of additional product candidates for other DMD mutations. Our planned follow-on programs for exons 53, 45 and 44 would provide therapeutic solutions for approximately 35% of all DMD patients.”

A second poster presentation titled Cas13d Multi-targeting Efficiently Targets Sense and Antisense HRE Containing Toxic RNAs and poly-GP DPR in C9ALS Patient Cells and in C9-BAC500 Mouse Model details studies with Locanabio’s Cas13d multi-targeting (Cas13d-MT) construct, which is designed to work with multiple guide RNAs to target both sense and antisense C9orf72 RNA transcripts that contain hexanucleotide repeat expansion (HRE) sequences. The data demonstrate that Cas13d-MT decreases both sense and antisense RNA foci in C9ALS patient-derived fibroblasts. The construct and guides can be packaged into a single AAV vector for efficient and durable delivery, which was evaluated in the C9-BAC500 disease model. Studies demonstrate robust Cas13d-MT transgene expression in spinal cord five weeks after administration with no evidence of toxicity, which translated into statistically significant reduction of both sense and antisense toxic HRE RNAs in the spinal cord. Results also showed a reduction of toxic RNA and dipeptides in the brain over six weeks of treatment. Importantly, due to the allele selective nature of the Cas13d payload, overall C9orf72 mRNA levels were preserved indicating that the non-repeat containing isoforms or wild-type allele of C9orf72 RNA transcripts are not targeted for destruction. The data support further development of this Cas13dMT AAV vector targeting toxic sense and antisense HRE sequences for the potential treatment of C9orf72 ALS as well as C9orf72 associated frontotemporal dementia.

Locanabio’s presentations at ASGCT are available on the Scientific Posters and Publications page of the company’s website.

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 C9orf72-related Amyotrophic Lateral Sclerosis (ALS)
C9orf72-related ALS is a genetic degenerative motor neuron disorder which accounts for approximately 40% of familial ALS and 10% of sporadic ALS. The estimated incidence of the disease in the U.S. is 1.5–2.2 cases per 100,000 people. ALS is caused by the degeneration of motor neurons that lead to progressive muscle wasting, weakness and muscle atrophy and eventual death from respiratory failure 2–5 years after diagnosis. The C9orf72 gene mutation is a repeated expansion of hexanucleotide sequences (G4C2 and C4G2) in the non-coding portion of the gene. Both the sense and antisense strands can be translated as dipeptides that are toxic to cells. In addition, the transcribed RNA forms secondary structures that may sequester regulatory RNA binding proteins (RBPs) and activate double-stranded RNA related stress response pathways. The C9orf72 mutation can also lead to frontotemporal dementia.

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

SOURCE: Locanabio