Gene Therapy Corrects Brain and Behavioral Pathologies in CLN6-Batten Disease

Mol Ther. 2019 Oct 2;27(10):1836-1847. doi: 10.1016/j.ymthe.2019.06.015. Epub 2019 Jul 10.


CLN6-Batten disease, a form of neuronal ceroid lipofuscinosis is a rare lysosomal storage disorder presenting with gradual declines in motor, visual, and cognitive abilities and early death by 12-15 years of age. We developed a self-complementary adeno-associated virus serotype 9 (scAAV9) vector expressing the human CLN6 gene under the control of a chicken β-actin (CB) hybrid promoter. Intrathecal delivery of scAAV9.CB.hCLN6 into the cerebrospinal fluid (CSF) of the lumbar spinal cord of 4-year-old non-human primates was safe, well tolerated, and led to efficient targeting throughout the brain and spinal cord. A single intracerebroventricular (i.c.v.) injection at post-natal day 1 in Cln6 mutant mice delivered scAAV9.CB.CLN6 directly into the CSF, and it prevented or drastically reduced all of the pathological hallmarks of Batten disease. Moreover, there were significant improvements in motor performance, learning and memory deficits, and survival in treated Cln6 mutant mice, extending survival from 15 months of age (untreated) to beyond 21 months of age (treated). Additionally, many parameters were similar to wild-type counterparts throughout the lifespan of the treated mice.

Keywords: adenovirus; gene rescue; neurodegenerative disease; neuronal ceroid lipofuscinosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / genetics
  • Animals
  • Dependovirus / genetics*
  • Genetic Therapy / methods*
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / adverse effects
  • Humans
  • Infusions, Intraventricular
  • Injections, Spinal
  • Learning / drug effects
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mice
  • Motor Activity / drug effects
  • Mutation
  • Neuronal Ceroid-Lipofuscinoses / genetics
  • Neuronal Ceroid-Lipofuscinoses / metabolism
  • Neuronal Ceroid-Lipofuscinoses / psychology*
  • Neuronal Ceroid-Lipofuscinoses / therapy*
  • Primates
  • Promoter Regions, Genetic
  • Treatment Outcome


  • Actins
  • CLN6 protein, human
  • Membrane Proteins

Supplementary concepts

  • Ceroid Lipofuscinosis, Neuronal, 6