Pharmacokinetics of ASO therapy in a mouse model of Usher syndrome
Publication Date
July 2019
Location
LSU Health Medical Education Building
Document Type
Abstract
Start Date
26-7-2019 9:00 AM
End Date
26-7-2019 12:00 PM
Description
Usher syndrome (Usher) is the most common inherited cause of deaf-blindness. Type 1 Usher is the most deverm form, characterized by hearing impairment at birth and retinitis pigmentosa (RP) beginning in early adolescence. 2.5% of Usher cases are caused by mutations in the USH1C gene, which encodes the protein harmonin. The function of harmonin in the retina and the cause of RP following its mutation are not known. The c.216G>A (216A) mutation in USH1C causes nearly all type I Usher in the Acadians of Louisiana and Canada. Previously, our lab created a knock-in mouse model that contains the human USH1C 216A mutation. The USH1C mice are deaf, and have vestibular and visual dysfunction similar to patients. We then developed antisense oligonucleotides (ASO) targeting the 216A mutation and showed that treatment with various deliveries and doses rescues hearing, balance and vision in the USH1C mice. To further develop this ASO therapy for the treatment of visual loss in patients, we sought to improve our understanding of the pharmacokinetics of ASOs after local injection in the eye. USH1C and control mice were treated with various doses of ASOs by intravitreal injection and ASO levels were quantitated in retinal tissues harvested 2 weeks post-treatment using HPLC and mass spectrometry. These results will inform future studies on the safety and biodistribution of ASOs in the retina after local treatment.
Recommended Citation
Fisher, Mark, "Pharmacokinetics of ASO therapy in a mouse model of Usher syndrome" (2019). Summer Research Internship Program. 11.
https://digitalscholar.lsuhsc.edu/srip/2019/undergrad/11
Pharmacokinetics of ASO therapy in a mouse model of Usher syndrome
LSU Health Medical Education Building
Usher syndrome (Usher) is the most common inherited cause of deaf-blindness. Type 1 Usher is the most deverm form, characterized by hearing impairment at birth and retinitis pigmentosa (RP) beginning in early adolescence. 2.5% of Usher cases are caused by mutations in the USH1C gene, which encodes the protein harmonin. The function of harmonin in the retina and the cause of RP following its mutation are not known. The c.216G>A (216A) mutation in USH1C causes nearly all type I Usher in the Acadians of Louisiana and Canada. Previously, our lab created a knock-in mouse model that contains the human USH1C 216A mutation. The USH1C mice are deaf, and have vestibular and visual dysfunction similar to patients. We then developed antisense oligonucleotides (ASO) targeting the 216A mutation and showed that treatment with various deliveries and doses rescues hearing, balance and vision in the USH1C mice. To further develop this ASO therapy for the treatment of visual loss in patients, we sought to improve our understanding of the pharmacokinetics of ASOs after local injection in the eye. USH1C and control mice were treated with various doses of ASOs by intravitreal injection and ASO levels were quantitated in retinal tissues harvested 2 weeks post-treatment using HPLC and mass spectrometry. These results will inform future studies on the safety and biodistribution of ASOs in the retina after local treatment.
Comments
Mentor: Jennifer J. Lentz, Ph.D.