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.
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.
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.
Produce functional protein through exon skipping or exon inclusion.
Knockdown and knockdown & replace
Exon skipping triggering nonsense-mediated decay (NMD) of the RNA transcript produced from toxic alleles.
Increase protein levels
Skip poison exons that contain premature stop codons to increase protein production, which can address haploinsufficiency or provide cellular protection.
Target toxic repeats to free sequestered endogenous proteins bound to these repeats.
Recruit endogenous ADARs (adenosine deaminases acting on RNA) to effect A to I (G) RNA editing.
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 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.