Intravitreal gene therapy protects against retinal dysfunction and degeneration in sheep with CLN5 Batten disease

Samantha J. Murray, Katharina N. Russell, Tracy R. Melzer, Steven J. Gray, Stephen J. Heap, David N. Palmer, Nadia L. Mitchell

Research output: Contribution to journalArticlepeer-review

Abstract

Neuronal ceroid lipofuscinoses (NCL; Batten disease) are a group of inherited neurodegenerative diseases primarily affecting children. A common feature across most NCLs is the progressive loss of vision. We performed intravitreal injections of self-complementary AAV9 vectors packaged with either ovine CLN5 or CLN6 into one eye of 3-month-old CLN5−/− or CLN6−/− animals, respectively. Electroretinography (ERG) was performed every month following treatment, and retinal histology was assessed post-mortem in the treated compared to untreated eye. In CLN5−/− animals, ERG amplitudes were normalised in the treated eye whilst the untreated eye declined in a similar manner to CLN5 affected controls. In CLN6−/− animals, ERG amplitudes in both eyes declined over time although the treated eye showed a slower decline. Post-mortem examination revealed significant attenuation of retinal atrophy and lysosomal storage body accumulation in the treated eye compared with the untreated eye in CLN5−/− animals. This proof-of-concept study provides the first observation of efficacious intravitreal gene therapy in a large animal model of NCL. In particular, the single administration of AAV9-mediated intravitreal gene therapy can successfully ameliorate retinal deficits in CLN5−/− sheep. Combining ocular gene therapy with brain-directed therapy presents a promising treatment strategy to be used in future sheep trials aiming to halt neurological and retinal disease in CLN5 Batten disease.

Original languageEnglish (US)
Article number108600
JournalExperimental Eye Research
Volume207
DOIs
StatePublished - Jun 2021

Keywords

  • AAV9
  • CLN5
  • CLN6
  • Electroretinography
  • Gene therapy
  • Intravitreal
  • Neuronal ceroid lipofuscinosis
  • Sheep

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

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