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ERG assessment of altered retinal function in canine models of retinitis pigmentosa and monitoring of response to translatable gene augmentation therapy

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Abstract

Purpose

To analyze ERG responses from two dog models of retinitis pigmentosa, one due to a PDE6A mutation and the other a CNGB1 mutation, both to assess the effect of these mutations on retinal function and the ability of gene augmentation therapy to restore normal function.

Methods

Scotopic and photopic ERGs from young affected and normal control dogs and affected dogs following AAV-mediated gene augmentation therapy were analyzed. Parameters reflecting rod and cone function were collected by modeling the descending slope of the a-wave to measure receptor response and sensitivity. Rod-driven responses were further assessed by Naka-Rushton fitting of the first limb of the scotopic b-wave luminance–response plot.

Results

PDE6A−/− dogs showed a dramatic decrease in rod-driven responses with very reduced rod maximal responses and sensitivity. There was a minor reduction in the amplitude of maximal cone responses. In contrast, CNGB1−/− dogs had some residual rod responses with reduced amplitude and sensitivity and normal cone responses. Following gene augmentation therapy, rod parameters were substantially improved in both models with restoration of sensitivity parameters log S and log K and a large increase in log Rmax in keeping with rescue of normal rod phototransduction in the treated retinal regions.

Conclusions

Modeling of rod and cone a-waves and the luminance–response function of the scotopic b-wave characterized the loss of rod photoreceptor function in two dog models of retinitis pigmentosa and showed the effectiveness of gene augmentation therapy in restoring normal functional parameters.

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References

  1. Petersen-Jones SM, Occelli LM, Winkler PA, Lee W, Sparrow JR, Tsukikawa M, Boye SL, Chiodo V, Capasso JE, Becirovic E, Schön C, Seeliger MW, Levin AV, Michalakis S, Hauswirth WW, Tsang SH (2018) Patients and animal models of CNGβ1-deficient retinitis pigmentosa support gene augmentation approach. J Clin Invest 128:190–206. https://doi.org/10.1172/JCI95161

    Article  PubMed  Google Scholar 

  2. Petersen-Jones SM, Komáromy AM (2015) Dog models for blinding inherited retinal dystrophies. Hum Gene Ther Clin Dev 26:15–26. https://doi.org/10.1089/humc.2014.155

    Article  CAS  PubMed  Google Scholar 

  3. Winkler PA, Occelli LM, Petersen-Jones SM (2020) Large animal models of inherited retinal degenerations: a review. Cells. https://doi.org/10.3390/cells9040882

    Article  PubMed  PubMed Central  Google Scholar 

  4. Somma AT, Moreno JCD, Sato MT, Rodrigues BD, Bacellar-Galdino M, Occelli LM, Petersen-Jones SM, Montiani-Ferreira F (2017) Characterization of a novel form of progressive retinal atrophy in Whippet dogs: a clinical, electroretinographic, and breeding study. Vet Ophthalmol 20:450–459. https://doi.org/10.1111/vop.12448

    Article  CAS  PubMed  Google Scholar 

  5. Occelli LM, Schön C, Seeliger MW, Biel M, Michalakis S, Petersen-Jones S, Consortium R-C (2017) Gene supplementation rescues rod function and preserves photoreceptor and retinal morphology in dogs, leading the way towards treating human PDE6A-retinitis pigmentosa. Hum Gene Ther. https://doi.org/10.1089/hum.2017.155

    Article  Google Scholar 

  6. Acland GM, Aguirre GD, Ray J, Zhang Q, Aleman TS, Cideciyan AV, Pearce-Kelling SE, Anand V, Zeng Y, Maguire AM, Jacobson SG, Hauswirth WW, Bennett J (2001) Gene therapy restores vision in a canine model of childhood blindness. Nat Genet 28:92–95. https://doi.org/10.1038/ng0501-92

    Article  CAS  PubMed  Google Scholar 

  7. Narfström K, Tullis GE, Seeliger M (2007) Effective treatment for the canine rpe65 null mutation, a hereditary retinal dystrophy comparable to human leber’s congenital amaurosis. In: Tombran-Tink J, Barnstable CJ (eds) Retinal degenerations. Humana Press, Totowa, NJ, pp 415–431

    Chapter  Google Scholar 

  8. Mowat FM, Petersen-Jones SM, Williamson H, Williams DL, Luthert PJ, Ali RR, Bainbridge JW (2008) Topographical characterization of cone photoreceptors and the area centralis of the canine retina. Mol Vis 14:2518–2527

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Beltran WA, Cideciyan AV, Guziewicz KE, Iwabe S, Swider M, Scott EM, Savina SV, Ruthel G, Stefano F, Zhang L, Zorger R, Sumaroka A, Jacobson SG, Aguirre GD (2014) Canine retina has a primate fovea-like bouquet of cone photoreceptors which is affected by inherited macular degenerations. PLoS ONE 9:e90390. https://doi.org/10.1371/journal.pone.0090390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Tuntivanich N, Pittler SJ, Fischer AJ, Omar G, Kiupel M, Weber A, Yao S, Steibel JP, Khan NW, Petersen-Jones SM (2009) Characterization of a canine model of autosomal recessive retinitis pigmentosa due to a PDE6A mutation. Invest Ophthalmol Vis Sci 50:801. https://doi.org/10.1167/iovs.08-2562

    Article  PubMed  Google Scholar 

  11. Winkler PA, Ekenstedt KJ, Occelli LM, Frattaroli AV, Bartoe JT, Venta PJ, Petersen-Jones SM (2013) A large animal model for CNGB1 autosomal recessive retinitis pigmentosa. PLoS ONE 8:e72229. https://doi.org/10.1371/journal.pone.0072229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hüttl S, Michalakis S, Seeliger M, Luo D-G, Acar N, Geiger H, Hudl K, Mader R, Haverkamp S, Moser M, Pfeifer A, Gerstner A, Yau K-W, Biel M (2005) Impaired channel targeting and retinal degeneration in mice lacking the cyclic nucleotide-gated channel subunit CNGB1. J Neurosci 25:130–138. https://doi.org/10.1523/JNEUROSCI.3764-04.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Marinho LLP, Occelli LM, Pasmanter N, Somma AT, Montiani-Ferreira F, Petersen-Jones SM (2019) Autosomal recessive night blindness with progressive photoreceptor degeneration in a dog model. Invest Ophthalmol Vis Sci 60:465–465

    Google Scholar 

  14. Pasmanter N, Petersen-Jones SM (2020) A review of electroretinography waveforms and models and their application in the dog. Vet Ophthalmol 23:418–435. https://doi.org/10.1111/vop.12759

    Article  PubMed  Google Scholar 

  15. Annear MJ, Bartoe JT, Barker SE, Smith AJ, Curran PG, Bainbridge JW, Ali RR, Petersen-Jones SM (2011) Gene therapy in the second eye of RPE65-deficient dogs improves retinal function. Gene Ther 18:53–61. https://doi.org/10.1038/gt.2010.111

    Article  CAS  PubMed  Google Scholar 

  16. Brigell M, Jeffrey BG, Mahroo OA, Tzekov R (2020) ISCEV extended protocol for derivation and analysis of the strong flash rod-isolated ERG a-wave. Doc Ophthalmol 140:5–12. https://doi.org/10.1007/s10633-019-09740-4

    Article  PubMed  Google Scholar 

  17. Hood DC, Birch DG (1996) Assessing abnormal rod photoreceptor activity with the a-wave of the electroretinogram: applications and methods. Doc Ophthalmol 92:253–267. https://doi.org/10.1007/BF02584080

    Article  PubMed  Google Scholar 

  18. Hood DC, Birch DG (1990) The A-wave of the human electroretinogram and rod receptor function. Invest Ophthalmol Vis Sci 31:2070–2081

    CAS  PubMed  Google Scholar 

  19. Hood DC, Birch DG (1995) Phototransduction in human cones measured using the a-wave of the ERG. Vision Res 35:2801–2810. https://doi.org/10.1016/0042-6989(95)00034-W

    Article  CAS  PubMed  Google Scholar 

  20. Robson JG, Maeda H, Saszik SM, Frishman LJ (2004) In vivo studies of signaling in rod pathways of the mouse using the electroretinogram. Vision Res 44:3253–3268. https://doi.org/10.1016/j.visres.2004.09.002

    Article  CAS  PubMed  Google Scholar 

  21. Naka KI, Rushton WAH (1966) S-potentials from luminosity units in the retina of fish (Cyprinidae). J Physiol 185:587–599. https://doi.org/10.1113/jphysiol.1966.sp008003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Naka KI, Rushton WAH (1967) The generation and spread of S-potentials in fish (Cyprinidae). J Physiol 192:437–461. https://doi.org/10.1113/jphysiol.1967.sp008308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Evans LS, Peachey NS, Marchese AL (1993) Comparison of three methods of estimating the parameters of the Naka-Rushton equation. Doc Ophthalmol 84:19–30

    Article  CAS  Google Scholar 

  24. Team PC (2015) Python: A dynamic, open source programming language. Python Software Foundation 78

  25. Newville M, Stensitzki T, Allen DB, Ingargiola A (2014) LMFIT: non-linear least-square minimization and curve-fitting for python. Zenodo

  26. Levenberg K (1944) A method for the solution of certain non-linear problems in least squares. Quart Appl Math 2:164–168. https://doi.org/10.1090/qam/10666

    Article  Google Scholar 

  27. Marquardt DW (1963) An Algorithm for Least-Squares Estimation of Nonlinear Parameters. J Soc Ind Appl Math 11:431–441. https://doi.org/10.1137/0111030

    Article  Google Scholar 

  28. Seabold, Skipper, Perktold, Josef (2010) Statsmodels: econometric and statistical modeling with python. Proceedings of the 9th Python in Science Conference

  29. Kaupp UB, Seifert R (2002) Cyclic nucleotide-gated ion channels. Physiol Rev 82:769–824. https://doi.org/10.1152/physrev.00008.2002

    Article  CAS  PubMed  Google Scholar 

  30. Bruewer AR, Mowat FM, Bartoe JT, Boye SL, Hauswirth WW, Petersen-Jones SM (2013) Evaluation of lateral spread of transgene expression following subretinal AAV-mediated gene delivery in dogs. PLoS ONE 8:e60218. https://doi.org/10.1371/journal.pone.0060218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bush RA, Sieving PA (1994) A proximal retinal component in the primate photopic ERG a-wave. Invest Ophthalmol Vis Sci 35:635–645

    CAS  PubMed  Google Scholar 

  32. Robson JG, Saszik SM, Ahmed J, Frishman LJ (2003) Rod and cone contributions to the a-wave of the electroretinogram of the macaque. J Physiol (Lond) 547:509–530. https://doi.org/10.1113/jphysiol.2002.030304

    Article  CAS  Google Scholar 

  33. Xu L, Ball SL, Alexander KR, Peachey NS (2003) Pharmacological analysis of the rat cone electroretinogram. Vis Neurosci 20:297–306. https://doi.org/10.1017/S0952523803203084

    Article  PubMed  Google Scholar 

  34. Sharma S, Ball SL, Peachey NS (2005) Pharmacological studies of the mouse cone electroretinogram. Vis Neurosci 22:631–636. https://doi.org/10.1017/S0952523805225129

    Article  PubMed  Google Scholar 

  35. Gauvin M, Lina J-M, Lachapelle P (2014) Advance in ERG analysis: from peak time and amplitude to frequency, power, and energy. Biomed Res Int 2014:1–11. https://doi.org/10.1155/2014/246096

    Article  Google Scholar 

  36. Gauvin M, Little JM, Lina J-M, Lachapelle P (2015) Functional decomposition of the human ERG based on the discrete wavelet transform. J Vis 15:14. https://doi.org/10.1167/15.16.14

    Article  PubMed  Google Scholar 

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Funding

This study was funded by NIH R24EY027285, Tistou and Charlotte Kerstan Stiftung, Myers-Dunlap Endowment (SMPJ is the Myers-Dunlap Endowed Chair in Canine Health).

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Authors and Affiliations

  1. Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, 736 Wilson Road, D-208, East Lansing, MI, 48824, USA

    Nate Pasmanter, Laurence M. Occelli & Simon M. Petersen-Jones

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  1. Nate Pasmanter
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  2. Laurence M. Occelli
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  3. Simon M. Petersen-Jones
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Corresponding author

Correspondence to Simon M. Petersen-Jones.

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Conflicts of interest

The authors declare that they have no conflicts of interest.

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The procedures in this study were approved by the Michigan State University Institutional Animal Care and Use Committee.

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Informed consent was not applicable.

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This article does not contain any studies with human participants performed by any of the authors.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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Pasmanter, N., Occelli, L.M. & Petersen-Jones, S.M. ERG assessment of altered retinal function in canine models of retinitis pigmentosa and monitoring of response to translatable gene augmentation therapy. Doc Ophthalmol 143, 171–184 (2021). https://doi.org/10.1007/s10633-021-09832-0

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  • DOI: https://doi.org/10.1007/s10633-021-09832-0

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