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  Neural plasticity of the human visual system reflects treatment effect in gene therapy for Achromatopsia

Seitz, I., Erb, M., Ethofer, T., Rina, A., Fischer, M., Keliris, G., et al. (2022). Neural plasticity of the human visual system reflects treatment effect in gene therapy for Achromatopsia. Investigative Ophthalmology and Visual Science, 63(7): 452.

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Seitz, IP, Author
Erb, M, Author              
Ethofer, T, Author
Rina, A, Author
Fischer, MD, Author
Keliris, GA1, Author              
Bartz-Schmidt, K-U, Author
Affiliations:
1Department Physiology of Cognitive Processes, Max Planck Institute for Biological Cybernetics, Max Planck Society, ou_1497798              

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 Abstract: Purpose : Achromatopsia (ACHM) is an inherited retinal disease marked by total cone photoreceptor dysfunction. Tübingen University Hospital completed a Phase I/II clinical trial evaluating the safety and efficacy of an AAV-based, subetinal gene therapy (GT) in adults affected by ACHM due to mutations in CNGA3. One year after GT for ACHM, patients demonstrated a significant, yet not clinically relevant, improvement of best-corrected visual acuity (BCVA) and contrast sensitivity (CS). Because ACHM patients are affected from birth, we hypothesized, that beyond retinal restitution of CNGA3 bioactivity, neural plasticity of the visual system could be a limiting factor in treatment response. To test this hypothesis, patients underwent diffusion tensor imaging (DTI), an established surrogate for white matter (WM) integrity and organization, prior to, and one year after GT. Methods : Nine patients were examined by a single operator, using a Siemens PRISMA 3T MRI device and a 64-channel head coil. Data processing relied on FSL and SPM12. Using DTI, we measured fractioned anisotropy (FA), a scalar value between 0 and 1, which denotes the directionality of diffusion, and mean diffusivity (MD), the mean speed of diffusion along all tensors. DTI, BCVA and CS measurements were taken prior to, and 1 year after GT. We then performed a voxel-wise regression analysis for ΔFA and ΔMD vs. ΔBCVA and ΔCS along the visual system, with a significance threshold of p<0.05, and rejection of small clusters (<25 voxels). Results : DTI imaging revealed multiple clusters (n=12) along the visual system, in which WM changes [ΔFA, ΔMD] and clinical treatment response [ΔBCVA, ΔCS] one year after GT displayed a moderate to strong (R2=0.47-0.74), and significant (p<0.05) correlation. This was the case for both BCVA (vs. FA R2=0.48-0.56, n=4 vs. MD R2=0.47-0.72, n=4), and CS (vs. FA R2=0.48-0.74, n=3, vs. MD R2=0.66, n=1). Conclusions : Despite a low effect size in adult ACHM patients, DTI revealed a significant correlation between the degree of BCVA and CS improvement, and the degree of WM plasticity in key areas of the visual system, one year after GT. This supports the notion, that neural plasticity might indeed be a limiting factor in the treatment response of adult ACHM patients. Based on these results, it seems sensible to treat younger patients, which harbor greater potential for a remodeling of the visual system.

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 Dates: 2022-06
 Publication Status: Published in print
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Title: Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO 2022)
Place of Event: Debver, CO, USA
Start-/End Date: 2022-05-01 - 2022-05-12

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Title: Investigative Ophthalmology and Visual Science
Source Genre: Journal
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Publ. Info: Hagerstown, MD, etc. : Association for Research in Vision and Ophthalmology, etc.
Pages: - Volume / Issue: 63 (7) Sequence Number: 452 Start / End Page: - Identifier: ISSN: 0146-0404
CoNE: https://pure.mpg.de/cone/journals/resource/110978984074949