Mutation-independent therapy for retinal degenerations caused by PRPH2 mutations

Summary
Expression of pathogenic variants in Peripherin-2 (PRPH2) leads to various forms of retinal dystrophies, with the
mechanisms of degeneration remaining poorly understood. However, studies in mouse models expressing
equivalent mutations have revealed the formation of aberrant outer segments with elongated dysmorphic discs.
With no approved treatments available and the complexity of pathogenic pathways involved, identifying a
universally effective therapeutic target for PRPH2 pathogenic variants is crucial.
The elongated disc formation suggests that the presence of the full complement of rhodopsin in the absence of
required amounts of PRPH2 is responsible. Thus, the therapeutic potential of reducing rhodopsin levels to
ameliorate the disease phenotype in various knockin models of PRPH2 pathogenic variants was explored.
Recently published proof-of-concept studies investigated partial genetic ablation of rhodopsin in mouse models
expressing PRPH2 mutations equivalent to patients' pathogenic variants K153∆ (c.458-460Del) and Y141C
(c.422A>G). These studies showed that reducing rhodopsin levels improved physiological function, mitigated the
severity of disc abnormalities, and decreased retinal gliosis. Additionally, and to determine the clinical
applicability, intravitreal injections of a rhodopsin-specific antisense oligonucleotide (mRho-ASO) in the mouse
model expressing the Y141C (c.422A>G) mutation enhanced the physiological function of photoreceptors and
improved disc ultrastructure.
The current proposal aims to:
1. Determine the applicability of mRho-ASO treatment to other knockin models expressing different mutant
forms of PRPH2.
2. Investigate the efficacy of external application of the therapeutic Rho-ASO.
First, a group of mice expressing PRPH2 with mutations C213Y, K153∆, or Prph2+/- will receive 1 µL of mRho-
ASO (6.25 mg/mL) at postnatal (P) 15 and another at P45, with assessment at P90. Second, the long-term
efficacy of a single mRho-ASO treatment will be evaluated at post-injection days (PI) 120 and 240. Third, the
efficacy of multiple treatments with the ASO at P15, 30, 45, and 60 will be assessed at P90. Fourth, the efficacy
of non-invasive eye drop application of the mRho-ASO will be evaluated for short-term (1 month PI) and long-
term (4 months PI) delivery in the Y141C model.
Outcomes will be assessed functionally by electroretinography and structurally by fundus imaging, OCT, light
microscopy, and electron microscopy for ultrastructural analysis. The levels of RHO and PRPH2 will be assessed
by immunodot blotting.
The successful implementation of this proposal will significantly influence the prognosis for patients afflicted with
vision loss stemming from variant PRPH2 expression.

Grant Number: 1R21EY037470-01
NIH Institute/Center: NIH
Principal Investigator: MUAYYAD AL-UBAIDI