CORRECTING DISEASE-CAUSING RNA
WITH A NEW APPROACH TO GENE THERAPY
Genetic diseases are caused by mutations in the genome, which can result in mutant RNA transcripts. Our platform of RNA binding systems can precisely target and correct these defective RNA transcripts. Delivered using AAV gene therapy vectors, this approach is designed to provide durable benefits to patients living with rare but devastating disorders—with the convenience of a single administration.
Focused Locanabio scientist conducting RNA-related research
CORRECTING DISEASE-CAUSING RNA
WITH A NEW APPROACH TO GENE THERAPY
Genetic diseases are caused by mutations in the genome, which can result in mutant RNA transcripts. Our platform of RNA binding systems can precisely target and correct these defective RNA transcripts. Delivered using AAV gene therapy vectors, this approach is designed to provide durable benefits to patients living with rare but devastating disorders—with the convenience of a single administration.

Our Platform

Our platform leverages the power and precision of RNA binding systems and AAV delivery, which provides a durable effect following single administration. Our platform is modular and versatile with several different RNA-targeting payloads for modifying disease-causing RNA using multiple mechanisms. The small size of our RNA binding systems enables multi-targeting, allowing for targeting of multiple sites on a single or multiple RNA transcripts. Additionally, our constructs can be designed to be allele selective, targeting only the mutant allele while preserving the wild-type allele. Our platform combines multiple attractive features that allow us to create novel therapies for patients with rare genetic neuromuscular and neurodegenerative diseases.

PRECISELY

targets and corrects disease-causing RNA

Multiple Mechanisms

to target and modify RNA

MULTI-TARGETING

capability to target multiple sequences in a single construct

DELIVERED

in a single gene therapy administration

snRNA PLATFORM

Our next generation vectorized snRNA platform leverages engineered small nuclear RNAs, or snRNAs, which target RNA exclusively and precisely. snRNAs naturally occur in human cells and are stabilized by endogenous cellular proteins. They are non-immunogenic and can effect a wide variety of mechanisms to target RNA. Their small size, at under 500 bp including promoter sequences, allows delivery of multiple snRNAs in a single AAV vector.
Modular structure of snRNA
The modular structure of snRNAs allows the replacement of the antisense targeting sequence(s) in a previously established vector backbone to facilitate the regulatory process for rapid product development.
We have developed unique know-how relating to the design of snRNA sequences, their packaging and manufacturing, enabling us to rapidly deploy this platform for our initial application of exon skipping in Duchenne muscular dystrophy, or DMD. Beyond this, snRNAs can be leveraged for several mechanisms and a broad set of indications.

Multi-mechanistic

Our programmable snRNA platform can modify disease-causing RNA via a number of mechanisms, providing an array of approaches to treat various genetic diseases. Due to the small size of our snRNAs, we can combine multiple mechanisms into a single AAV vector.
Frame restoration
Produce functional protein through exon skipping or exon inclusion.
Frame restoration (a way Locanabio can modify disease-causing RNA)
Knockdown and knockdown & replace
Exon skipping triggering nonsense-mediated decay (NMD) of the RNA transcript produced from toxic alleles.
Knockdown and knockdown & replace (ways Locanabio can modify disease-causing RNA)
Increase protein levels
Skip poison exons that contain premature stop codons to increase protein production, which can address haploinsufficiency or provide cellular protection.
Increased protein levels (a way Locanabio can modify disease-causing RNA)
Repeat blocking
Target toxic repeats to free sequestered endogenous proteins bound to these repeats.
Repeat blocking (a way Locanabio can modify disease-causing RNA)
RNA editing
Recruit endogenous ADARs (adenosine deaminases acting on RNA) to effect A to I (G) RNA editing.
RNA editing (a way Locanabio can modify disease-causing RNA)

Multi-targeting

The small size of snRNAs allows us to design and package constructs that can target multiple sequences across one or more mutant RNA transcripts into a single AAV vector.
The dual snRNA, or 2x snRNA, construct expresses two snRNAs carrying 4 different RNA targeting sequences
The dual snRNA, or 2x snRNA, construct expresses two snRNAs carrying four different RNA targeting sequences. Thus the 2x snRNAs are able to target 1-4 different sites on the same or different RNA transcripts, which would otherwise require multiple therapies.
This multi-targeting capability can be applied two different ways:
Enhanced targeting of a single transcript:
We can identify multiple sequences of interest within the transcript and program targeting sequences accordingly. Multi-targeting is valuable in the treatment of DMD, where targeting multiple splicing regulatory elements improves the exon-skipping efficiency for a single exon and may enable a multi-exon skipping approach to address a broader patient population of DMD patients.
Targeting multiple RNA transcripts with a single vector:
This has the potential to create “combination” therapies that would otherwise require two or more different drugs.

AAV gene therapy – durable benefit following single administration

We deliver snRNA using AAV, which provides durable response with a single administration of the payload potentially enabling a single administration. The high level of potency of our snRNA designs potentially enables dosing at lower levels compared to other gene therapies. In addition, AAV gene therapy is clinically well understood and cGMP AAV manufacturing well-established.

RNA-binding proteins

In addition to our programs leveraging the programmable snRNA platform, certain of our programs employ RNA-binding proteins. We leverage two different proteins as payloads, Cas13d and programmable PUF proteins. Both target RNA exclusively and can be designed to precisely target the intended RNA sequence(s) for blocking or destruction, which we use for applications such as repeat expansion disorders including DM1 and C9 ALS. Both payloads are small and fit into a single AAV vector, can be programmed to be allele selective and have the ability to effect multi-targeting.
Cas13d protein
Cas13d
RNA-specific
Cas proteins
  • Targets RNA exclusively
  • Uses guide RNA (gRNA) for precise targeting and can process multiple gRNAs
  • 3 kb size = single AAV vector
  • Requires no cellular machinery
Programmable PUF protein
PUF
Programmable and
modular RNA-binding
proteins
  • Targets RNA exclusively
  • Human origin—no guide RNA (gRNA) needed
  • Programmable for different target sequences and MOAs
  • Requires no cellular machinery
  • 1.4 kb size = single AAV vector
SCIENTIFIC POSTERS & PUBLICATIONS