Substantial restoration of night vision in adult mice with congenital stationary night blindness

Abstract

Complete congenital stationary night blindness (cCSNB) due to mutations in TRPM1 , GRM6 , GPR179 , NYX , or leucine-rich repeat immunoglobulin-like transmembrane domain 3 ( LRIT3 ) is an incurable inherited retinal disorder characterized by an ON-bipolar cell (ON-BC) defect. Since the disease is non-degenerative and stable, treatment could theoretically be administrated at any time in life, making it a promising target for gene therapy. Until now, adeno-associated virus (AAV)-mediated therapies lead to significant functional improvements only in newborn cCSNB mice. Here we aimed to restore protein localization and function in adult Lrit3 −/ − mice. LRIT3 localizes in the outer plexiform layer and is crucial for TRPM1 localization at the dendritic tips of ON-BCs and the electroretinogram (ERG)-b-wave. AAV2-7m8- Lrit3 intravitreal injections were performed targeting either ON-BCs, photoreceptors (PRs), or both. Protein localization of LRIT3 and TRPM1 at the rod-to-rod BC synapse, functional rescue of scotopic responses, and ON-responses detection at the ganglion cell level were achieved in a few mice when ON-BCs alone or both PRs and ON-BCs, were targeted. More importantly, a significant number of treated adult Lrit3 −/− mice revealed an ERG b-wave recovery under scotopic conditions, improved optomotor responses, and on-time ON-responses at the ganglion cell level when PRs were targeted. Functional rescue was maintained for at least 4 months after treatment.

Targeting ON-bipolar cells by AAV gene therapy stably reverses LRIT3 -congenital stationary night blindness

“…In our study, subretinal injection of the vector–promoter–reporter constructs in NHP clearly demonstrated ON-BC expression. However, prior to moving toward clinical trials with our ON-BC targeting vector, it will be critically important to determine if targeting photoreceptors instead of ON-BCs results in comparable treatment efficacy as in mice ( 35 , 36 ).…”

“…In a recent report by Varin et al. ( 36 ), adult Lrit3 nob6 mice were treated intravitreally using AAV2-7m8- Lrit3 , targeting ON-BCs alone, photoreceptors alone, or both (OPL) by interchanging cell-specific promoters. Restoration of LRIT3 and TRPM1 localization and functional rescue were demonstrated in only a fraction (7 to 25%) of the treated mice ( SI Appendix , Table S1 ).…”

LRIT3 expression in cone photoreceptors restores post-synaptic bipolar cell signalplex assembly and function in Lrit3-/- mice

“…The functional rescue of the CSNB phenotype by expressing LRIT3 in rods and cones supports a role of LRIT3 as a trans-synaptic organizer of the DBC signalplex, although two reports suggest partial rescue may be possible by expressing LRIT3 in DBCs. Zeitz and colleagues used AAV mediated expression of LRIT3 using DBC or photoreceptor specific promoters to restore function in Lrit3 nob6 mice (Varin et al ., 2021). Some ERG rescue was present in animals when LRIT3 expression was targeted to DBCs, although the extent of scotopic ERG rescue was greater when photoreceptors were targeted (Varin et al ., 2021).…”

“…This unexpected result suggests that LRIT3 can act as a trans-synaptic organizer of the post-synaptic signalplex. Two other studies, one in mouse and one in dog LRIT3 deficient models, restored rod BC signalplex function using postsynaptic targeting of LRIT3 (Miyadera et al, 2022; Varin et al, 2021).…”

Gene therapies for retinal dystrophies: potential in the Chinese population

“…Varin et al, 2021 26 France LRIT3 LRIT3 -/mice received intravitreal injections of recombinant AAVs.…”