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Dr. Carroll: Advances in Retinal Imaging of Achromatopsia
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Dr. Carroll: Advances in Retinal Imaging of Achromatopsia


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  • 1. Advances in Retinal Imaging of Achromatopsia
    Joseph Carroll, PhD
    Departments of Ophthalmology, Biophysics, and Cell Biology, Neurobiology, & Anatomy Medical College of Wisconsin
    Achromatopsia Convention
    August 2, 2011
  • 2. Acknowledgements
    Medical College of Wisconsin
    Kim Stepien, MD
    Alf Dubra, PhD
    JungtaeRha, PhD
    Robert Cooper
    Adam Dubis
    Brett Schroeder
    Phyllis Summerfelt
    Chicago Lighthouse/UIC
    Gerald Fishman, MD
    Mohamed Genead, MD
    University of Washington
    Jay Neitz, PhD
    Maureen Neitz, PhD
    $$$$ - NIH EY017607, EY001931, Research to Prevent Blindness, E. Matilda Ziegler Foundation for the Blind, Kirchgessner Foundation, Gene & Ruth Posner Foundation, RD & Linda Peters Foundation, Hope for Vision, Vision for Tomorrow Foundation, & Fight for Sight
  • 3. Complex layered structure which is made up of different types of cells.
    Picture from Webvision: The Organization of the Retina and Visual System
  • 4.
  • 5. Webvision
    Ann Milam
    Fine & Yanoff (1979)
  • 6.
  • 7. In achromatopsia, we are interested in studying photoreceptor structure – as this is likely to be helpful in the translation of gene-based therapies to the condition.
    Two imaging techniques have emerged that allow us to directly assess photoreceptor structure in patients with achromatopsia and other retinal disorders…
  • 8. Optical Coherence Tomography
  • 9. Adaptive Optics
    • Used in astronomy to correct for turbulence in the atmosphere.
  • Spot Array
    Wave Aberration
    The Human Eye is Highly Aberrated
    Ideal, Diffraction-Limited Eye
    Normal, Aberrated Eye
    Courtesy: Jason Porter
  • 10. Carroll et al., (2005)
  • 11. Adaptive Optics Imaging
    30 deg
    3 deg
    2 mm resolution
  • 12. Imaging the Rod and Cone Mosaic
    Dubra, Sulai, Norris, Cooper, Dubis, Williams, Carroll(2011)
  • 13. With the ability to resolve the entire photoreceptor mosaic, we can quantify different aspects of the rod and cone mosaics…
    Dubra, Sulai, Norris, Cooper, Dubis, Williams, Carroll(2011)
  • 14. Recent success in retinal gene therapy indicate that it may be possible to restore cone function in individuals with ACHM and BCM:
    • modest visual function recovered in patients with LCA (Maguire et al., 2008; Bainbridge et al., 2008; Cideciyanet al., 2008),
    • 15. cone function improved in dog and mouse models of congenital achromatopsia (Komáromyet al., 2010; Alexander et al., 2007),
    • 16. trichromatic color vision achieved in a primate model of human dichromacy (Mancuso et al., 2009)
    A better understanding of photoreceptor structure is needed in order to assess the therapeutic potential in human patients with AHCM & BCM.
  • 17. Achromatopsia
    • Autosomal recessive; ≈1 in 33,000 incidence
    • 18. Caused by defect in CNGA3, CNG3, GNAT2, or PDE6C.
    • 19. Affected individuals are thought to have no cone function (though see Nishiguchi, et al. 2005).
    • 20. Clinically presents very similarly to BCM.
    • 21. Histology data varies: from suggesting normal peripheral cones (Larsen, 1921), reduced numbers throughout (Harrison et al., 1960; Glickstein & Heath, 1975), or normal numbers in the fovea (Falls et al., 1965).
    • 22. OCT data suggests progressive loss of cone layers (Thiadens et al. 2010)…
  • IS
  • 23. Variable IS/OS Photoreceptor Structure Present in ACHM
    Geneadet al. (2011)
  • 24. Foveal Hypoplasia
  • 25. Assessing Cone Structure in ACHM
    Geneadet al. (2011)
  • 26. Assessing Cone Structure in ACHM
    Geneadet al. (2011)
  • 27.
  • 28. Variation in cone structure within individual retina.
    Geneadet al. (2011)
  • 29. ACHM: Imaging Summary
    • OCT reveals foveal hypoplasia in a number of patients. Unclear what the link is to the pathophysiology of achromatopsia is.
    • 30. OCT reveals significant variation in the disruption of the IS/OS, and variable thinning of the ONL – suggesting variable degrees of photoreceptor loss.
    • 31. Imaging with AO reveals significant cone structure in most patients, with some even retaining both an inner and outer segment to the cone. These cones are not functioning normally, but appear to be intact structurally, at least in part.
    • 32. Significant work remains:
    • 33. Examine differences across genotypes
    • 34. Examine longitudinal cone loss in these conditions
    • 35. Correlate structural differences with functional measures
  • abs
    Normal Human Color Vision
    Hofer et al. (2006)
  • 36. Blue Cone Monochromacy
    • Rare X-linked condition characterized
    by an absence of L- and M-cone function.
    - (L + M) = ~95% of all cones
    • Individuals with BCM present with poor
    color discrimination, reduced central vision,
    nystagmus, & myopia, but otherwise normal fundus findings.
    • Two primary genetic pathways in BCM – “one-step” involve a deletion of the LCR whereas “two-step” include a reduction in gene number to 1 and incorporation of a missense mutation in the remaining opsin gene.
    - Accumulating evidence for macular atrophy and progressive loss of visual function in BCM (Ayyagari et al., 1999, 2000; Kellner et al., 2004; Michaelides et al., 2004; Mizrahi-Meissonnier et al., 2010).
    Hofer et al. (2005)
  • 37. BCM
  • 38. JC0184
    13 yrs
    16 yrs
    31 yrs
    mm (OD)
  • 39. S-Cone Free Zone
  • 40. JC_0183
    Curcio et al. (1991)
    2,626 cones/mm2
    4,116 cones/mm2
    2,000 – 5,000 cones/mm2
    S-Cone Free Zone
    - Data is consistent with the S-cone free zone being variable in size (Williams et al., 1981; de Monasterioet al., 1985; Norket al., 1990; Curcio et al., 1991).
    - Residual packing density of S-cones may contribute to phenotypic heterogeneity.
  • 41. Peripheral BCM Mosaic
    Rods begin to appear.
    Large, bright S cones no longer visible, rather cones appear dark (inner segment). Fewer in number than AHCM.
  • 42. ACHM & BCM
    • It appears that there are reliable imaging biomarkers that distinguish these two conditions:
    • 43. BCM has thinner ONL than ACHM
    • 44. S-cone free zone visible in BCM, not ACHM
    • 45. No foveal hypoplasia seen in BCM
    • 46. As genetic testing can often be inconclusive and expensive, use of high resolution imaging to guide genetic testing may be helpful.
    • 47. Imaging the retina in both conditions may be an important part of the success of emerging treatments – both in selecting patients and in monitoring outcomes.
  • Challenges Ahead
    • Need for continued imaging of patients with a variety of presentations with documented genotypes.
    • 48. Continued development of hardware that will allow more routine imaging of the retina in patients with nystagmus.
    • 49. Need for better software for more robust analysis of retinal images – still evolving.
    • 50. Need to expand access to high-resolution imaging tools.
    • 51. All of this requires commitment and investment from funding agencies, researchers, and patients alike.