Cell penetrating peptides for the delivery of ASOs to the neural retina across rodents and NHPs  — ASN Events
  1. Schedule
  2. Poster Session 1 - Wine Tasting
  3. Cell penetrating peptides for the delivery of ASOs to the neural retina across rodents and NHPs 

Cell penetrating peptides for the delivery of ASOs to the neural retina across rodents and NHPs  (#210)

Mark Anastasas 1 , Adam Martin 1 , Emily Woodward 1 , Sue Fletcher 1 2 , Sing Yee Yeung 1 , Clinton Hall 1 , Kristin Priebatsch 1 , Hoang Vo 1 , Anna Mills 1 , Maria Kerfoot 1 , Meenu Chopra 1 , Paula Cunningham 1
  1. PYC Therapeutics, Nedlands, WA, Australia
  2. Murdoch University, Perth, Australia

One of the biggest challenges currently facing the extrahepatic application of antisense therapies is that of intracellular delivery. Despite recent advances in antisense oligonucleotide (ASO) chemistries which render these versatile molecules more potent, more cell permeable and more selective, challenges still remain in the areas of off-target tissue distribution and perhaps most importantly, intracellular delivery. Cell penetrating peptides offer an effective route to intracellular delivery, with multiple cell-penetrating peptide-PMOs (PPMOs) currently in clinical development.  

 

PYC Therapeutics proprietary cell penetrating peptide Platform has been used to deliver a ASOs to extrahepatic tissues. In the eye, PYC’s PPMO candidates show excellent target engagement in the rodent and rabbit neural retina, at tolerated doses. In the mouse eye, a first-generation PPMO (1x) and 2’MOE (1x, 10x and 30x) targeting survival motor neuron (Smn) exon 7 exclusion were administered and eyes harvested 7-, 14-, and 28-days following intravitreal injection.

 

The PPMO was detected in the retina at 28 days with associated Smn exon 7 skipping, indicating intracellular penetration. The 2'-MOE was homogeneously distributed across the retina over the same timeframe, however the 2'-MOE induced minimal Smn exon 7 skipping, suggesting lower cellular uptake. To achieve similar exon skipping to the PPMO, 60-fold and 5-fold higher concentrations of 2'-MOE were required in the neural retina and RPE, respectively (day 28 analyses).  

 

This first generation PPMO and PYC’s second generation PPMO were subsequently evaluated in a larger rabbit eye, with intravitreal administration of PYC’s second generation PPMO (same Smn target gene) exhibiting a threefold improvement in target engagement, at a threefold lower dose, in the rabbit neural retina.

 

Both the PK and PD profiles observed indicate that PYC’s CPPs are an enabling ocular delivery platform and form the basis for PYC’s clinical and preclinical programs across retinitis pigmentosa type 11 and autosomal dominant optic atrophy. 

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