Longitudinal In Vivo Monitoring of the CNS Demonstrates the Efficacy of Gene Therapy in a Sheep Model of CLN5 Batten Disease

Mol Ther. 2018 Oct 3;26(10):2366-2378. doi: 10.1016/j.ymthe.2018.07.015. Epub 2018 Jul 17.


Neuronal ceroid lipofuscinoses (NCLs; Batten disease) are neurodegenerative lysosomal storage diseases predominantly affecting children. Single administration of brain-directed lentiviral or recombinant single-stranded adeno-associated virus 9 (ssAAV9) vectors expressing ovine CLN5 into six pre-clinically affected sheep with a naturally occurring CLN5 NCL resulted in long-term disease attenuation. Treatment efficacy was demonstrated by non-invasive longitudinal in vivo monitoring developed to align with assessments used in human medicine. The treated sheep retained neurological and cognitive function, and one ssAAV9-treated animal has been retained and is now 57 months old, almost triple the lifespan of untreated CLN5-affected sheep. The onset of visual deficits was much delayed. Computed tomography and MRI showed that brain structures and volumes remained stable. Because gene therapy in humans is more likely to begin after clinical diagnosis, self-complementary AAV9-CLN5 was injected into the brain ventricles of four 7-month-old affected sheep already showing early clinical signs in a second trial. This also halted disease progression beyond their natural lifespan. These findings demonstrate the efficacy of CLN5 gene therapy, using three different vector platforms, in a large animal model and, thus, the prognosis for human translation.

Keywords: AAV and lentiviral gene therapy; NCLs; in vivo monitoring; maze testing; neuronal ceroid lipofuscinosis; sheep brain CT and MRI; sheep neurological scoring.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / diagnostic imaging
  • Brain / drug effects*
  • Brain / physiopathology
  • Dependovirus / genetics
  • Disease Models, Animal
  • Genetic Therapy*
  • Humans
  • Lysosome-Associated Membrane Glycoproteins
  • Lysosomes / genetics
  • Magnetic Resonance Imaging
  • Membrane Proteins / genetics*
  • Membrane Proteins / therapeutic use
  • Neuronal Ceroid-Lipofuscinoses / diagnostic imaging
  • Neuronal Ceroid-Lipofuscinoses / genetics
  • Neuronal Ceroid-Lipofuscinoses / pathology
  • Neuronal Ceroid-Lipofuscinoses / therapy*
  • Sheep
  • Tomography, X-Ray Computed


  • CLN5 protein, human
  • Lysosome-Associated Membrane Glycoproteins
  • Membrane Proteins