Intracranial delivery of AAV9 gene therapy partially prevents retinal degeneration and visual deficits in CLN6-Batten disease mice

Katherine A White; Hemanth R Nelvagal; Timothy A Poole; Bin Lu; Tyler B Johnson; Samantha Davis; Melissa A Pratt; Jon Brudvig; Ana B Assis; Shibi Likhite; Kathrin Meyer; Brian K Kaspar; Jonathan D Cooper; Shaomei Wang; Jill M Weimer

doi:10.1016/j.omtm.2020.12.014

Intracranial delivery of AAV9 gene therapy partially prevents retinal degeneration and visual deficits in CLN6-Batten disease mice

Mol Ther Methods Clin Dev. 2021 Jan 5:20:497-507. doi: 10.1016/j.omtm.2020.12.014. eCollection 2021 Mar 12.

Authors

Katherine A White¹, Hemanth R Nelvagal^{2

3}, Timothy A Poole², Bin Lu⁴, Tyler B Johnson^{1

5}, Samantha Davis¹, Melissa A Pratt¹, Jon Brudvig¹, Ana B Assis³, Shibi Likhite⁶, Kathrin Meyer^{7

8}, Brian K Kaspar^{7

8}, Jonathan D Cooper^{2

3}, Shaomei Wang⁴, Jill M Weimer^{1

5

9}

Affiliations

¹ Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD 57104, USA.
² Pediatric Storage Disorders Laboratory, Division of Genetics and Genomics, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
³ Department of Pediatrics, The Lundquist Institute at Harbor-UCLA Medical Center and David Geffen School of Medicine, UCLA, Torrance, CA 90502, USA.
⁴ Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
⁵ Amicus Therapeutics, Philadelphia, PA 19104, USA.
⁶ Nationwide Children's Hospital. He was involved in AAV9 construct development.
⁷ The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
⁸ Department of Pediatrics, The Ohio State University, Columbus, OH 43210, USA.
⁹ Department of Pediatrics, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD 57069, USA.

Abstract

Batten disease is a family of rare, fatal, neuropediatric diseases presenting with memory/learning decline, blindness, and loss of motor function. Recently, we reported the use of an AAV9-mediated gene therapy that prevents disease progression in a mouse model of CLN6-Batten disease (Cln6 ^nclf ), restoring lifespans in treated animals. Despite the success of our viral-mediated gene therapy, the dosing strategy was optimized for delivery to the brain parenchyma and may limit the therapeutic potential to other disease-relevant tissues, such as the eye. Here, we examine whether cerebrospinal fluid (CSF) delivery of scAAV9.CB.CLN6 is sufficient to ameliorate visual deficits in Cln6 ^nclf mice. We show that intracerebroventricular (i.c.v.) delivery of scAAV9.CB.CLN6 completely prevents hallmark Batten disease pathology in the visual processing centers of the brain, preserving neurons of the superior colliculus, thalamus, and cerebral cortex. Importantly, i.c.v.-delivered scAAV9.CB.CLN6 also expresses in many cells throughout the central retina, preserving many photoreceptors typically lost in Cln6 ^nclf mice. Lastly, scAAV9.CB.CLN6 treatment partially preserved visual acuity in Cln6 ^nclf mice as measured by optokinetic response. Taken together, we report the first instance of CSF-delivered viral gene reaching and rescuing pathology in both the brain parenchyma and retinal neurons, thereby partially slowing visual deterioration.

Keywords: AAV9; Batten disease; CLN6; Gene therapy; ICV; NCL; retina; vision.

Abstract

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