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Molecular Genetics Laboratory

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Ting Xiao

Surname Xiao
First name Ting
Position and Title Visiting Scientist
Project The AON based uORF blockage in the expression of OPA1——a pre-clinical development of therepy for OPA1-linked optic atrophy

Business address

Molecular Genetics Laboratory
Institute for Ophthalmic Research
Centre for Ophthalmology,
University of Tübingen
Elfriede-Aulhorn-Strasse 7
D-72076 Tübingen,
Germany

Phone: +49 (0)7071 29-80706

E-mail: ting.xiao[at]med.uni-tuebingen.de

Project descriptions

The AON based uORF blockage in the expression of OPA1——a pre-clinical development of therepy for OPA1-linked optic atrophy

Autosomal dominant optic atrophy (adOA) is a hereditary bilateral optic neuropathy, characterized by the isolated degeneration of retinal ganglion cells (RGCs) and the atrophy of optic nerve. Patients with adOA often present insidious and progressive vison loss at the early school age, central visual field defects and handicap in blue-yellow color discrimination. Moreover, some patients even show syndromic symptoms like deafness, chronic progressive external ophthalmoplegia and ataxia. OPA1 is the major pathogenic gene for adOA. The OPA1 gene, localized on 3q28, spans more than 100 kb and includes 31exons (including exons 4b and 5b) encoding 960 amino acids. The large GTPase OPA1 is anchored to the inner mitochondrial membrane and has been ascribed to participate in various functions, including mitochondrial DNA maintenance, tethering of the cristae junctions and most importantly: fusion of the inner mitochondrial membrane. Molecular analyses of patients with heterozygous OPA1 mutations suggest haploinsufficiency is the major pathomechanism for OPA1 related optic atrophy. However, so far, there’s no effective therapy for OPA1-linked optic neuropathy.

Upstream open reading frame (uORF) which is a short protein-coding element located in the 5′ UTR region of downstream primary ORF (pORF). And it is common in eukaryotic genes that can be found in human (49%) and mouse (44%) transcripts. Recent studies showed that the existence of the uORF leads to the greatly reduced protein expression. An antisense oligonucleotides (AONs) based technology targeting uORF can increase the amout of the protein translated from the pORF both in human and mouse cells. In terms of our recent study, we found that in the 5′ UTR region of OPA1 gene, there is a uORF which is highly conserved in mammalian animals. Therefore, we proposed a hypothesis that the uORF of the OPA1 gene probably plays a negative regulation role in OPA1 translation. Blocking the uORF of OPA1 may result in increased OPA1 expression.

My project is “The AON based uORF blockage in the expression of OPA1——a pre-clinical development of therepy for OPA1-linked optic atrophy”. In this project, we try to prove the negative effect of uORF on OPA1 and subsequently use the AON targeting the uORF to increase the expression of OPA1 in vitro and in vivo. Thus, provide a potential therapy for OPA1-linked optic atrophy.