A demonstration of cone function plasticity after gene therapy in achromatopsia
© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain..
Recent advances in regenerative therapy have placed the treatment of previously incurable eye diseases within arms' reach. Achromatopsia is a severe monogenic heritable retinal disease that disrupts cone function from birth, leaving patients with complete colour blindness, low acuity, photosensitivity and nystagmus. While successful gene-replacement therapy in non-primate models of achromatopsia has raised widespread hopes for clinical treatment, it was yet to be determined if and how these therapies can induce new cone function in the human brain. Using a novel multimodal approach, we demonstrate for the first time that gene therapy can successfully activate dormant cone-mediated pathways in children with achromatopsia (CNGA3- and CNGB3-associated, 10-15 years). To test this, we combined functional MRI population receptive field mapping and psychophysics with stimuli that selectively measure cone photoreceptor signalling. We measured cortical and visual cone function before and after gene therapy in four paediatric patients, evaluating treatment-related change against benchmark data from untreated patients (n = 9) and normal-sighted participants (n = 28). After treatment, two of the four children displayed strong evidence for novel cone-mediated signals in visual cortex, with a retinotopic pattern that was not present in untreated achromatopsia and which is highly unlikely to emerge by chance. Importantly, this change was paired with a significant improvement in psychophysical measures of cone-mediated visual function. These improvements were specific to the treated eye, and provide strong evidence for successful read-out and use of new cone-mediated information. These data show for the first time that gene replacement therapy in achromatopsia within the plastic period of development can awaken dormant cone-signalling pathways after years of deprivation. This reveals unprecedented neural plasticity in the developing human nervous system and offers great promise for emerging regenerative therapies.
Medienart: |
E-Artikel |
---|
Erscheinungsjahr: |
2022 |
---|---|
Erschienen: |
2022 |
Enthalten in: |
Zur Gesamtaufnahme - volume:145 |
---|---|
Enthalten in: |
Brain : a journal of neurology - 145(2022), 11 vom: 21. Nov., Seite 3803-3815 |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Farahbakhsh, Mahtab [VerfasserIn] |
---|
Links: |
---|
Themen: |
Achromatopsia |
---|
Anmerkungen: |
Date Completed 23.11.2022 Date Revised 14.02.2024 published: Print Citation Status MEDLINE |
---|
doi: |
10.1093/brain/awac226 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
NLM345173902 |
---|
LEADER | 01000caa a22002652 4500 | ||
---|---|---|---|
001 | NLM345173902 | ||
003 | DE-627 | ||
005 | 20240214232551.0 | ||
007 | cr uuu---uuuuu | ||
008 | 231226s2022 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1093/brain/awac226 |2 doi | |
028 | 5 | 2 | |a pubmed24n1292.xml |
035 | |a (DE-627)NLM345173902 | ||
035 | |a (NLM)35998912 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Farahbakhsh, Mahtab |e verfasserin |4 aut | |
245 | 1 | 2 | |a A demonstration of cone function plasticity after gene therapy in achromatopsia |
264 | 1 | |c 2022 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a ƒaComputermedien |b c |2 rdamedia | ||
338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
500 | |a Date Completed 23.11.2022 | ||
500 | |a Date Revised 14.02.2024 | ||
500 | |a published: Print | ||
500 | |a Citation Status MEDLINE | ||
520 | |a © The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. | ||
520 | |a Recent advances in regenerative therapy have placed the treatment of previously incurable eye diseases within arms' reach. Achromatopsia is a severe monogenic heritable retinal disease that disrupts cone function from birth, leaving patients with complete colour blindness, low acuity, photosensitivity and nystagmus. While successful gene-replacement therapy in non-primate models of achromatopsia has raised widespread hopes for clinical treatment, it was yet to be determined if and how these therapies can induce new cone function in the human brain. Using a novel multimodal approach, we demonstrate for the first time that gene therapy can successfully activate dormant cone-mediated pathways in children with achromatopsia (CNGA3- and CNGB3-associated, 10-15 years). To test this, we combined functional MRI population receptive field mapping and psychophysics with stimuli that selectively measure cone photoreceptor signalling. We measured cortical and visual cone function before and after gene therapy in four paediatric patients, evaluating treatment-related change against benchmark data from untreated patients (n = 9) and normal-sighted participants (n = 28). After treatment, two of the four children displayed strong evidence for novel cone-mediated signals in visual cortex, with a retinotopic pattern that was not present in untreated achromatopsia and which is highly unlikely to emerge by chance. Importantly, this change was paired with a significant improvement in psychophysical measures of cone-mediated visual function. These improvements were specific to the treated eye, and provide strong evidence for successful read-out and use of new cone-mediated information. These data show for the first time that gene replacement therapy in achromatopsia within the plastic period of development can awaken dormant cone-signalling pathways after years of deprivation. This reveals unprecedented neural plasticity in the developing human nervous system and offers great promise for emerging regenerative therapies | ||
650 | 4 | |a Journal Article | |
650 | 4 | |a Research Support, Non-U.S. Gov't | |
650 | 4 | |a achromatopsia | |
650 | 4 | |a fMRI | |
650 | 4 | |a gene therapy | |
650 | 4 | |a photoreceptors | |
650 | 4 | |a visual cortex | |
650 | 7 | |a Cyclic Nucleotide-Gated Cation Channels |2 NLM | |
700 | 1 | |a Anderson, Elaine J |e verfasserin |4 aut | |
700 | 1 | |a Maimon-Mor, Roni O |e verfasserin |4 aut | |
700 | 1 | |a Rider, Andy |e verfasserin |4 aut | |
700 | 1 | |a Greenwood, John A |e verfasserin |4 aut | |
700 | 1 | |a Hirji, Nashila |e verfasserin |4 aut | |
700 | 1 | |a Zaman, Serena |e verfasserin |4 aut | |
700 | 1 | |a Jones, Pete R |e verfasserin |4 aut | |
700 | 1 | |a Schwarzkopf, D Samuel |e verfasserin |4 aut | |
700 | 1 | |a Rees, Geraint |e verfasserin |4 aut | |
700 | 1 | |a Michaelides, Michel |e verfasserin |4 aut | |
700 | 1 | |a Dekker, Tessa M |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t Brain : a journal of neurology |d 1945 |g 145(2022), 11 vom: 21. Nov., Seite 3803-3815 |w (DE-627)NLM000126292 |x 1460-2156 |7 nnns |
773 | 1 | 8 | |g volume:145 |g year:2022 |g number:11 |g day:21 |g month:11 |g pages:3803-3815 |
856 | 4 | 0 | |u http://dx.doi.org/10.1093/brain/awac226 |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |d 145 |j 2022 |e 11 |b 21 |c 11 |h 3803-3815 |