Intrathecal Gene Therapy for Giant Axonal Neuropathy
Copyright © 2024 Massachusetts Medical Society..
BACKGROUND: Giant axonal neuropathy is a rare, autosomal recessive, pediatric, polysymptomatic, neurodegenerative disorder caused by biallelic loss-of-function variants in GAN, the gene encoding gigaxonin.
METHODS: We conducted an intrathecal dose-escalation study of scAAV9/JeT-GAN (a self-complementary adeno-associated virus-based gene therapy containing the GAN transgene) in children with giant axonal neuropathy. Safety was the primary end point. The key secondary clinical end point was at least a 95% posterior probability of slowing the rate of change (i.e., slope) in the 32-item Motor Function Measure total percent score at 1 year after treatment, as compared with the pretreatment slope.
RESULTS: One of four intrathecal doses of scAAV9/JeT-GAN was administered to 14 participants - 3.5×1013 total vector genomes (vg) (in 2 participants), 1.2×1014 vg (in 4), 1.8×1014 vg (in 5), and 3.5×1014 vg (in 3). During a median observation period of 68.7 months (range, 8.6 to 90.5), of 48 serious adverse events that had occurred, 1 (fever) was possibly related to treatment; 129 of 682 adverse events were possibly related to treatment. The mean pretreatment slope in the total cohort was -7.17 percentage points per year (95% credible interval, -8.36 to -5.97). At 1 year after treatment, posterior mean changes in slope were -0.54 percentage points (95% credible interval, -7.48 to 6.28) with the 3.5×1013-vg dose, 3.23 percentage points (95% credible interval, -1.27 to 7.65) with the 1.2×1014-vg dose, 5.32 percentage points (95% credible interval, 1.07 to 9.57) with the 1.8×1014-vg dose, and 3.43 percentage points (95% credible interval, -1.89 to 8.82) with the 3.5×1014-vg dose. The corresponding posterior probabilities for slowing the slope were 44% (95% credible interval, 43 to 44); 92% (95% credible interval, 92 to 93); 99% (95% credible interval, 99 to 99), which was above the efficacy threshold; and 90% (95% credible interval, 89 to 90). Between 6 and 24 months after gene transfer, sensory-nerve action potential amplitudes increased, stopped declining, or became recordable after being absent in 6 participants but remained absent in 8.
CONCLUSIONS: Intrathecal gene transfer with scAAV9/JeT-GAN for giant axonal neuropathy was associated with adverse events and resulted in a possible benefit in motor function scores and other measures at some vector doses over a year. Further studies are warranted to determine the safety and efficacy of intrathecal AAV-mediated gene therapy in this disorder. (Funded by the National Institute of Neurological Disorders and Stroke and others; ClinicalTrials.gov number, NCT02362438.).
Medienart: |
E-Artikel |
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Erscheinungsjahr: |
2024 |
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Erschienen: |
2024 |
Enthalten in: |
Zur Gesamtaufnahme - volume:390 |
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Enthalten in: |
The New England journal of medicine - 390(2024), 12 vom: 21. März, Seite 1092-1104 |
Sprache: |
Englisch |
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Beteiligte Personen: |
Bharucha-Goebel, Diana X [VerfasserIn] |
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Links: |
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Anmerkungen: |
Date Completed 22.03.2024 Date Revised 05.04.2024 published: Print ClinicalTrials.gov: NCT02362438 Citation Status MEDLINE |
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doi: |
10.1056/NEJMoa2307952 |
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funding: |
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Förderinstitution / Projekttitel: |
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PPN (Katalog-ID): |
NLM369973380 |
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245 | 1 | 0 | |a Intrathecal Gene Therapy for Giant Axonal Neuropathy |
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500 | |a published: Print | ||
500 | |a ClinicalTrials.gov: NCT02362438 | ||
500 | |a Citation Status MEDLINE | ||
520 | |a Copyright © 2024 Massachusetts Medical Society. | ||
520 | |a BACKGROUND: Giant axonal neuropathy is a rare, autosomal recessive, pediatric, polysymptomatic, neurodegenerative disorder caused by biallelic loss-of-function variants in GAN, the gene encoding gigaxonin | ||
520 | |a METHODS: We conducted an intrathecal dose-escalation study of scAAV9/JeT-GAN (a self-complementary adeno-associated virus-based gene therapy containing the GAN transgene) in children with giant axonal neuropathy. Safety was the primary end point. The key secondary clinical end point was at least a 95% posterior probability of slowing the rate of change (i.e., slope) in the 32-item Motor Function Measure total percent score at 1 year after treatment, as compared with the pretreatment slope | ||
520 | |a RESULTS: One of four intrathecal doses of scAAV9/JeT-GAN was administered to 14 participants - 3.5×1013 total vector genomes (vg) (in 2 participants), 1.2×1014 vg (in 4), 1.8×1014 vg (in 5), and 3.5×1014 vg (in 3). During a median observation period of 68.7 months (range, 8.6 to 90.5), of 48 serious adverse events that had occurred, 1 (fever) was possibly related to treatment; 129 of 682 adverse events were possibly related to treatment. The mean pretreatment slope in the total cohort was -7.17 percentage points per year (95% credible interval, -8.36 to -5.97). At 1 year after treatment, posterior mean changes in slope were -0.54 percentage points (95% credible interval, -7.48 to 6.28) with the 3.5×1013-vg dose, 3.23 percentage points (95% credible interval, -1.27 to 7.65) with the 1.2×1014-vg dose, 5.32 percentage points (95% credible interval, 1.07 to 9.57) with the 1.8×1014-vg dose, and 3.43 percentage points (95% credible interval, -1.89 to 8.82) with the 3.5×1014-vg dose. The corresponding posterior probabilities for slowing the slope were 44% (95% credible interval, 43 to 44); 92% (95% credible interval, 92 to 93); 99% (95% credible interval, 99 to 99), which was above the efficacy threshold; and 90% (95% credible interval, 89 to 90). Between 6 and 24 months after gene transfer, sensory-nerve action potential amplitudes increased, stopped declining, or became recordable after being absent in 6 participants but remained absent in 8 | ||
520 | |a CONCLUSIONS: Intrathecal gene transfer with scAAV9/JeT-GAN for giant axonal neuropathy was associated with adverse events and resulted in a possible benefit in motor function scores and other measures at some vector doses over a year. Further studies are warranted to determine the safety and efficacy of intrathecal AAV-mediated gene therapy in this disorder. (Funded by the National Institute of Neurological Disorders and Stroke and others; ClinicalTrials.gov number, NCT02362438.) | ||
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650 | 7 | |a GAN protein, human |2 NLM | |
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700 | 1 | |a Saade, Dimah |e verfasserin |4 aut | |
700 | 1 | |a Norato, Gina |e verfasserin |4 aut | |
700 | 1 | |a Jain, Minal |e verfasserin |4 aut | |
700 | 1 | |a Lehky, Tanya |e verfasserin |4 aut | |
700 | 1 | |a Bailey, Rachel M |e verfasserin |4 aut | |
700 | 1 | |a Chichester, Jessica A |e verfasserin |4 aut | |
700 | 1 | |a Calcedo, Roberto |e verfasserin |4 aut | |
700 | 1 | |a Armao, Diane |e verfasserin |4 aut | |
700 | 1 | |a Foley, A Reghan |e verfasserin |4 aut | |
700 | 1 | |a Mohassel, Payam |e verfasserin |4 aut | |
700 | 1 | |a Tesfaye, Eshetu |e verfasserin |4 aut | |
700 | 1 | |a Carlin, Bradley P |e verfasserin |4 aut | |
700 | 1 | |a Seremula, Beth |e verfasserin |4 aut | |
700 | 1 | |a Waite, Melissa |e verfasserin |4 aut | |
700 | 1 | |a Zein, Wadih M |e verfasserin |4 aut | |
700 | 1 | |a Huryn, Laryssa A |e verfasserin |4 aut | |
700 | 1 | |a Crawford, Thomas O |e verfasserin |4 aut | |
700 | 1 | |a Sumner, Charlotte J |e verfasserin |4 aut | |
700 | 1 | |a Hoke, Ahmet |e verfasserin |4 aut | |
700 | 1 | |a Heiss, John D |e verfasserin |4 aut | |
700 | 1 | |a Charnas, Lawrence |e verfasserin |4 aut | |
700 | 1 | |a Hooper, Jody E |e verfasserin |4 aut | |
700 | 1 | |a Bouldin, Thomas W |e verfasserin |4 aut | |
700 | 1 | |a Kang, Elizabeth M |e verfasserin |4 aut | |
700 | 1 | |a Rybin, Denis |e verfasserin |4 aut | |
700 | 1 | |a Gray, Steven J |e verfasserin |4 aut | |
700 | 1 | |a Bönnemann, Carsten G |e verfasserin |4 aut | |
700 | 0 | |a GAN Trial Team |e verfasserin |4 aut | |
700 | 1 | |a Bönnemann, Carsten G |e investigator |4 oth | |
700 | 1 | |a Bharucha-Goebel, Diana X |e investigator |4 oth | |
700 | 1 | |a Todd, Joshua J |e investigator |4 oth | |
700 | 1 | |a Saade, Dimah |e investigator |4 oth | |
700 | 1 | |a Norato, Gina |e investigator |4 oth | |
700 | 1 | |a Jain, Mina |e investigator |4 oth | |
700 | 1 | |a Lehky, Tanya |e investigator |4 oth | |
700 | 1 | |a Foley, A Reghan |e investigator |4 oth | |
700 | 1 | |a Mohassel, Payam |e investigator |4 oth | |
700 | 1 | |a Waite, Melissa |e investigator |4 oth | |
700 | 1 | |a Heiss, John D |e investigator |4 oth | |
700 | 1 | |a Averion, Gilberto |e investigator |4 oth | |
700 | 1 | |a Hu, Ying |e investigator |4 oth | |
700 | 1 | |a Mendoza, Christopher |e investigator |4 oth | |
700 | 1 | |a Brooks, Kia |e investigator |4 oth | |
700 | 1 | |a Yarish, Alexa |e investigator |4 oth | |
700 | 1 | |a Arevalo, Cynthia |e investigator |4 oth | |
700 | 1 | |a Donkervoort, Sandra |e investigator |4 oth | |
700 | 1 | |a Soldatos, Ariane |e investigator |4 oth | |
700 | 1 | |a Leach, Meganne |e investigator |4 oth | |
700 | 1 | |a Zou, Yaqun |e investigator |4 oth | |
700 | 1 | |a Jacobson, Steven |e investigator |4 oth | |
700 | 1 | |a Delong, Thomas |e investigator |4 oth | |
700 | 1 | |a Acquaye, Nicole |e investigator |4 oth | |
700 | 1 | |a Fink, Margaret |e investigator |4 oth | |
700 | 1 | |a Dastgir, Jahannaz |e investigator |4 oth | |
700 | 1 | |a Neuhaus, Sarah |e investigator |4 oth | |
700 | 1 | |a Paredes, Eduardo |e investigator |4 oth | |
700 | 1 | |a McCarty, Riley |e investigator |4 oth | |
700 | 1 | |a Jones, Christine |e investigator |4 oth | |
700 | 1 | |a Syeda, Safoora |e investigator |4 oth | |
700 | 1 | |a Hinkley, Lauren |e investigator |4 oth | |
700 | 1 | |a Debs, Sarah |e investigator |4 oth | |
700 | 1 | |a Yun, Pomi |e investigator |4 oth | |
700 | 1 | |a Reich, Daniel |e investigator |4 oth | |
700 | 1 | |a Nath, Avindra |e investigator |4 oth | |
700 | 1 | |a Yousef, Muhammad |e investigator |4 oth | |
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700 | 1 | |a Butman, John A |e investigator |4 oth | |
700 | 1 | |a Matsubara, Jesse |e investigator |4 oth | |
700 | 1 | |a Zampieri-Gallagher, Christiane |e investigator |4 oth | |
700 | 1 | |a Quezado, Zenaide |e investigator |4 oth | |
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700 | 1 | |a Damiano, Diane |e investigator |4 oth | |
700 | 1 | |a Bulea, Thomas |e investigator |4 oth | |
700 | 1 | |a Gravunder, Andrew |e investigator |4 oth | |
700 | 1 | |a Stanley, Christopher |e investigator |4 oth | |
700 | 1 | |a Vasavada, Ruhi |e investigator |4 oth | |
700 | 1 | |a Biancavilla, Victoria |e investigator |4 oth | |
700 | 1 | |a Mebrahtu, Aron |e investigator |4 oth | |
700 | 1 | |a Solomon, Beth |e investigator |4 oth | |
700 | 1 | |a Zein, Wadih M |e investigator |4 oth | |
700 | 1 | |a Huryn, Laryssa |e investigator |4 oth | |
700 | 1 | |a Wiggs, Edythe |e investigator |4 oth | |
700 | 1 | |a Kang, Elizabeth M |e investigator |4 oth | |
700 | 1 | |a Gray, Steven J |e investigator |4 oth | |
700 | 1 | |a Bailey, Rachel M |e investigator |4 oth | |
700 | 1 | |a Crawford, Thomas O |e investigator |4 oth | |
700 | 1 | |a Sumner, Charlotte J |e investigator |4 oth | |
700 | 1 | |a Hoke, Ahmet |e investigator |4 oth | |
700 | 1 | |a Chichester, Jessica A |e investigator |4 oth | |
700 | 1 | |a Hooper, Jody E |e investigator |4 oth | |
700 | 1 | |a Armao, Diane |e investigator |4 oth | |
700 | 1 | |a Bouldin, Thomas W |e investigator |4 oth | |
700 | 1 | |a Samulski, Richard Jude |e investigator |4 oth | |
700 | 1 | |a Whitehead, Matthew |e investigator |4 oth | |
700 | 1 | |a Rybin, Denis |e investigator |4 oth | |
700 | 1 | |a Charnas, Lawrence |e investigator |4 oth | |
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700 | 1 | |a Carlin, Bradley P |e investigator |4 oth | |
700 | 1 | |a Calcedo, Roberto |e investigator |4 oth | |
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