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Next-generation optogenetics to cure blindness

English title Next-generation optogenetics to cure blindness
Applicant Kleinlogel Sonja
Number 152807
Funding scheme Project funding (Div. I-III)
Research institution Institut für Physiologie Medizinische Fakultät Universität Bern
Institution of higher education University of Berne - BE
Main discipline Neurophysiology and Brain Research
Start/End 01.04.2014 - 30.09.2017
Approved amount 462'899.00
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All Disciplines (8)

Discipline
Neurophysiology and Brain Research
Molecular Biology
Genetics
Cellular Biology, Cytology
Biomedical Engineering
Ophthalmology
Physiology : other topics
Biophysics

Keywords (13)

bipolar cell; Retinitis pigmentosa; ophthalmology; gene therapy; metabotropic gluatmate receptors; optogenetics; melanopsin; Age-related macular degeneration; recombinant adeno-associated virus; vision recovery; retinal physiology; photoreceptor degeneration; molecular engineering

Lay Summary (German)

Lead
Das Absterben der Fotorezeptoren, der lichtempfinldichen Zellen des Auges, sind die Hauptursache von Blindheit. Bis heute gibt es noch keine Therapie, die das verlorene Sehvermögen wiederherstellen kann. Das Projekt untersucht eine neue Therapieform, die Augenzellen wieder lichtsensitiv machen kann.
Lay summary

Elektronische Netzhautimplantate, die seit 2013 vermarktet werden, sind die einzige existierende Therapie für Erblindete, welche an Fotorezeptordegeneration leiden. Diese elektronischen Chips bringen jedoch nur über einen kleinen Sehausschnitt und sehr rudimentär das Sehvermögen zurück. Mit anderen Worten, der behandelte Patient kann zwar wieder ein Hindernis, zum Beispiel eine Mauer, als Schatten erkennen, ist aber nicht in der Lage eine Zeitung zu lesen oder ein Auto zu fahren. Auch der operative Eingriff zum Platzieren des Chips trägt Risiken weiterer Augenschädigung für den Patienten mit sich.

Aus diesen Gründen  wird in den letzten Jahren auf veschiedenen Gebieten der Biologie- , Medizin- & Ingenieurwissenschaften nach einer verbesserten Therapieform geforscht.

Die Optogenetik ist die wohl vielversprechendste Methodik, in der lichtaktivierbare Proteine genetisch in bestimmte Zielzellen eingebracht werden, so dass diese Zellen danach lichtaktivierbar werden. Das Gen, welches für das optogenetische Protein kodiert, wird in einen nicht-pathogenen Virus verpackt und dem Patienten ambulant ins Auge eingespritzt, eine ungefährliche und gängige Injektionsmethode. Die Gentherapie ist eine zukunftsträchtige Methode, die in der Klinik erste positivie Anwendungen verzeichnet.

Wir haben biotechnologisch ein optogenetisches Protein fürs Auge konstruiert, welches die überlebenden Zellen der Netzhaut in Lichtsensoren verwandelt, so dass die Funktion der verlorenen Fotorezeptoren weitgehend ersetzt werden kann. In diesem Projekt wird dieses Protein nun für eine potentielle klinische Anwendung optimiert und gleichzeitig eine effiziente Gentherapie entwickelt.

Direct link to Lay Summary Last update: 03.04.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Present Molecular Limitations of ON-Bipolar Cell Targeted Gene Therapy.
van Wyk Michiel, Hulliger EC, Girod L, Ebneter A, Kleinlogel S (2017), Present Molecular Limitations of ON-Bipolar Cell Targeted Gene Therapy., in Frontiers in Neuroscience, 11, 116.
Optogenetics for Vision Recovery: From Traditional to Designer Optogenetic Tools.
Kleinlogel Sonja (2017), Optogenetics for Vision Recovery: From Traditional to Designer Optogenetic Tools., in Appasani Krishnarao (ed.), 327-355.
Chronic activation of the D156A point mutant of Channelrhodopsin-2 signals apoptotic cell death: the good and the bad.
Perny Michael, Muri Lukas, Dawson Heather, Kleinlogel Sonja (2016), Chronic activation of the D156A point mutant of Channelrhodopsin-2 signals apoptotic cell death: the good and the bad., in Cell Death and Disease, 7, e2447.
Embryonic Cell Grafts in a Culture Model of Spinal Cord Lesion: Neuronal Relay Formation Is Essential for Functional Regeneration.
Tscherter Anne, Heidemann Martina, Kleinlogel Sonja, Streit Jürg (2016), Embryonic Cell Grafts in a Culture Model of Spinal Cord Lesion: Neuronal Relay Formation Is Essential for Functional Regeneration., in Frontiers in Cellular Neuroscience, 10, 220.
Optogenetic user’s guide to Opto-GPCRs
Kleinlogel Sonja (2016), Optogenetic user’s guide to Opto-GPCRs, in Frontiers in Biosciences, 21, 794-805.
Variable phenotypic expressivity in inbred retinal degeneration mouse lines: A comparative study of C3H/HeOu and FVB/N rd1 mice.
van Wyk Michiel, Schneider Sabine, Kleinlogel Sonja (2015), Variable phenotypic expressivity in inbred retinal degeneration mouse lines: A comparative study of C3H/HeOu and FVB/N rd1 mice., in Molecular Vision, 21, 811-827.
Restoring the ON-switch in blind retinas: Opto-mGluR6, a next-generation optogenetic tool.
van Wyk Michiel, Pielecka-Fortuna Justyna, Löwel Siegrid, Kleinlogel Sonja (2015), Restoring the ON-switch in blind retinas: Opto-mGluR6, a next-generation optogenetic tool., in PLoS Biology, 13(5), e1002143.

Collaboration

Group / person Country
Types of collaboration
Dr. rer. nat. Hildegard Büning, Head "Vector Development Lab", ZMMK, Universitätsklinikum Köln Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Prof. Dr. Dr. S. Wolf, Klinik für Augenheilkunde, Inselspital Bern Switzerland (Europe)
- Research Infrastructure
Prof. Dr. Siegrid Löwel, Systems Neuroscience Group, Universität Göttingen Germany (Europe)
- Publication
- Research Infrastructure
Haag Streit Medtech AG Switzerland (Europe)
- Industry/business/other use-inspired collaboration

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
EMBO course on “Non-neuronal optogenetics” Talk given at a conference Customizing microbial and vertrabrate opsins for clinical investigations 02.09.2017 Heidelberg, Germany Kleinlogel Sonja;
Swiss Eye Research Week Talk given at a conference Present molecular limitations of ON-bipolar cell targeted gene therapy 26.01.2017 Neuchatel, Switzerland Kleinlogel Sonja; Hulliger Elmar;
FENS Talk given at a conference Optogenetic designer tool for vision recovery 01.07.2016 Copenhagen, Denmark Kleinlogel Sonja;
Neurotech Talk given at a conference Light in Sight 28.06.2016 Tübingen, Germany Kleinlogel Sonja;
EMBO Kurs "Non-neuronal optogenetics" Talk given at a conference Engineered, light-activated GPCRs for vision restoration 29.05.2016 Heidelberg, Germany Kleinlogel Sonja;
European Retina Meeting Talk given at a conference Vision restoration with a bipolar cell tailored optogentic tool 01.10.2015 Brighton, Great Britain and Northern Ireland Kleinlogel Sonja;
Molecular Mechanisms of neurodegeneration Talk given at a conference Optogenetic therapy for vision recovery 28.05.2015 Milan, Italy Kleinlogel Sonja;


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Fortbildung Augenklinik Lindenhofspital Talk 16.11.2016 Bern, Switzerland Kleinlogel Sonja;
Fortbildung Augenklinik Inselspital Talk 23.05.2016 Bern, Switzerland Kleinlogel Sonja;
NEURIZONS Talk 01.05.2016 Göttingen, Germany Kleinlogel Sonja;
Fortbilgund Augenklinik: Ungewöhnliche Einbliche Talk 17.03.2016 Zürich, Switzerland Kleinlogel Sonja;


Awards

Title Year
Theodor-Kocher-Prize from the University of Bern 2016
Swiss OphthAward from the Swiss Society of Ophthalmology 2015

Associated projects

Number Title Start Funding scheme
176065 Illuminating the capacity of optogenetically restored vision 01.11.2017 Project funding (Div. I-III)
176065 Illuminating the capacity of optogenetically restored vision 01.11.2017 Project funding (Div. I-III)

Abstract

Background: Optogenetics is the combination of genetic and optical methods to control the activity of genetically targeted cells of living tissue remotely by light1. The traditional optogenetic tools are microbial ion channels (i.e. Channelrhodopsin-2, ChR2) and ion pumps (i.e. Halorhodopsin, eNphR), which are heterologously introduced into the target cell types using molecular and genetic methods. Optogenetics has in the last few years revolutionized the field of neuroscience, being elected as Method of the Year by “Nature Methods” in 2010. The clinical potential of a handful of existing optogenetic tools is actively investigated at many fronts. Having a profound knowledge in this field, I am aware of their limitations, which will hinder their use in the clinic. It is thus imperative to develop next-generation light-activatable proteins, engineered to be safe, specialized and potent enough to be employed clinically. About one in three hundred people suffer from complete or partial blindness as a result of photoreceptor loss associated with diseases such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD), for which presently very limited treatment exists. Due to the light-accessibility and the low immunogenicity of the retina, optogenetics is a prime candidate technology for treating blindness. The goal of this investigation is to develop a gene therapy with a next-generation, custom-made optogenetic tool for retinal bipolar cells, which can render them directly light-sensitive to replace the function of the degenerated photoreceptors. Hypothesis:1)Opto-mGluR6 fulfills all the clinical requirements: non-immunogenic, non-toxic and function in photopic light conditions (major improvement compared to traditional optogenetic tools)2)Opto-mGluR6 recovers the visual function in the retina as well as the cortex with high visual resolution (major improvement compared to retinal implants)3)The Opto-mGluR6 gene therapy is transferrable into human tissue Methods: Recovery of retinal visual function will be determined in Opto-mGluR6 treated mice suffering from Retinitis pigmentosa by patch-clamp and electroretinogram recordings. Functional integrity of higher visual centers will be evaluated by behavioral (optomoter reflex, Morris water maze) functional cortical imaging experiments. In parallel, optimized rAAVs will be engineered to reach near-complete infection of the patient’s ON bipolar cells. The methodology will then be transferred into human post-mortem tissue. To suffice clinical requirements, toxicology and immunology studies on Opto-mGluR6 gene-therapeutically treated mice will be performed.Specific Aims:1.To prove that Opto-mGluR6 recovers the natural visual signal transduction cascade within the retina - and thus nearly perfect contrast vision - by simply replacing the missing light-sensor (photoreceptor cells).2.To engineer an optimal rAAV for retinal ON bipolar cells3.To optimize Opto-mGluR6 for human tissue (codon-optimization, specific promoter identification,…)4.To prove that the Opto-mGluR6 gene therapy is non-toxic and non-immunogenic5.To develop a product so ready for clinical trials.Significance: Opto-mGluR6 could bring back high-quality vision to blind patients suffering from photoreceptor degenerative diseases allowing for tasks such as driving a car or reading a book, whilst the only available treatment presently, retinal implants, only allow patients to distinguish high contrast edges to for example avoid an obstacle. This project combines two highly promising and emerging fields in regenerative medicine and in particular ophthalmology, which are rAAV gene therapy and optogenetics. The here proposed project optimizes the two technologies and aims to generate in just 3 years a product suited for clinical trials.
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