PORTEFEUILLE

Our goal is restore visual function in patients suffering in retinitis pigmentosa, using optogenetic technologies.

Retinitis pigmentosa (RP) collectively refers to a diverse group of progressive, hereditary rare diseases of the retina that lead to incurable blindness and affect two million people worldwide. Artificial photoreceptors constructed by expressing light-activated channels or pumps (‘optogenetic tools’) in surviving cell types in the retinal circuit have been shown to restore photosensitivity in animal models of RP. Our work here focuses on making efficient transfer of optogenetic tools to selected cell types in the retina and restoring color vision in animal models of RP. We believe that the results we obtain will bring optogenetic vision restoration closer to clinical use.

The novel idea underlying optogenetic vision restoration is the use of light sensors from microbes to create artificial photoreceptors in the retina. The rational for using these sensors is that microbes use a single protein to detect and signal light while in mammals the interaction of more than ten proteins is needed for this purpose.

We have made more than 200 new targeting vectors to selectively express optogenetic tools in different retinal cell types. We tested several of these vectors in vivo in the retinas in blind mice as well as in the retinas of wild type mice. We found about 20 different AAV vectors that target specific cell types or combination of cell types. We now have AAV vectors that can target cones, rods, Muller cells, some bipolar cell types, several amacrine cells types and several ganglion cell types in mice. A number of these AAVs are currently tested for targeted gene therapy applications. GenSight Biologics will translate cell type targeted gene therapy to human patients.

Yonehara K, Fiscella M, Drinnenberg A, Esposti F, Trenholm S, Krol J, Franke F, Scherf BG, Kusnyerik A, Müller J, Szabo A, Jüttner J, Cordoba F, Reddy AP, Németh J, Nagy ZZ, Munier F, Hierlemann A, Roska B. Congenital Nystagmus Gene FRMD7 Is Necessary for Establishing a Neuronal Circuit Asymmetry for Direction Selectivity. Neuron. 2016 Jan 6;89(1):177-93.
Krol J, Krol I, Alvarez CP, Fiscella M, Hierlemann A, Roska B* and Filipowicz W*. A network comprising short and long noncoding RNAs and RNA helicase controls mouse retina architecture. (*shared corresponding authors) Nature Communications 2015 Jun 4;6:7305.
Szikra T, Trenholm S, Drinnenberg A, Juettner J, Raics Z, Farrow K, Biel M, Awatramani G, Clark D, Sahel JA, da Silveira RA, Roska B During daylight rods act as relay cells conveying cone-driven horizontal cell-mediated surround inhibition to downstream visual circuits. Nature Neuroscience. 2014, 17(12):1728-35.
Busskamp V, Krol J, Nelidova D, Daum J, Szikra T, Tsuda B, Juettner J, Farrow K, Gross Scherf B, Patino Alvarez CP, Genoud C, Sothilingam V, Tanimoto N, Stadler M, Seeliger M, Stoffel M, Filipowicz W*, Roska B* MiRNAs 182 and 183 are necessary to maintain adult cone photoreceptor outer segments and visual function (*shared corresponding authors) Neuron. 2014, 83(3):586-600.
Cronin T, Vandenberghe LH, Hantz P, Juttner J, Reimann A, Kacsó AE, Huckfeldt RM, Busskamp V, Kohler H, Lagali PS, Roska B, Bennett J. Efficient transduction and optogenetic stimulation of retinal bipolar cells by a synthetic adeno-associated virus capsid and promoter. EMBO Mol Med. 2014 Aug 4;6(9):1175-90.
Busskamp V, Duebel J, Balya D, Fradot M, Viney TJ, Siegert S, Groner AC, Cabuy E, Forster V, Seeliger M, Biel M, Humphries P, Paques M, Mohand-Said S, Trono D, Deisseroth K, Sahel JA, Picaud S, Roska B. Genetic reactivation of cone photoreceptors restores visual responses in retinitis pigmentosa. Science. 2010 Jul 23;329(5990):413-7.
Lagali PS, Balya D, Awatramani GB, Münch TA, Kim DS, Busskamp V, Cepko CL, Roska B. Light-activated channels targeted to ON bipolar cells restore visual function in retinal degeneration. Nature Neurosci. 2008 Jun;11(6):667-75.
Siegert S, Cabuy E, Scherf BG, Kohler H, Panda S, Le YZ, Fehling HJ, Gaidatzis D, Stadler MB, Roska B. Transcriptional code and disease map for adult retinal cell types. Nature Neurosci. 2012 Jan
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Yonehara K, Farrow K, Ghanem A, Hillier D, Balint K, Teixeira M, Jüttner J, Noda M, Neve R, Conzelmann KK, Roska B. The first stage of cardinal direction selectivity is localized to the dendrites of retinal ganglion cells. Neuron. 2013, 79(6):1078-85.
Busskamp V, Krol J, Nelidova D, Daum J, Szikra T, Tsuda B, Juettner J, Farrow K, Gross Scherf B, Patino Alvarez CP, Genoud C, Sothilingam V, Tanimoto N, Stadler M, Seeliger M, Stoffel M, Filipowicz W*, Roska B* MiRNAs 182 and 183 are necessary to maintain adult cone photoreceptor outer segments and visual function (*shared corresponding authors) Neuron. 2014 Jul 4. [Epub ahead of print].

Eye disease tracked to a glitch in starburst cells, Novartis Nerd Blog, 9 May 2016
Defect retinal computation linked to congenital nystagmus, FMI News, 6 January 2016
Inducing visual function, FMI News 4 July 2014
First to measure the concerted activity of a neuronal circuit, FMI News 22 August 2013
Seeing the Light of Day, Science, 23 July 2010
Microbial protein restores vision in blind animals, FMI News, 25 June 2010
Blind mice see the ligth, Nature, 25 April 2008
Media Release, Novartis 28 April 2008