TY - JOUR
T1 - Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy
AU - Yu-Wai-Man, Patrick
AU - Newman, Nancy J.
AU - Carelli, Valerio
AU - Moster, Mark L.
AU - Biousse, Valerie
AU - Sadun, Alfredo A.
AU - Klopstock, Thomas
AU - Vignal-Clermont, Catherine
AU - Sergott, Robert C.
AU - Rudolph, Günther
AU - la Morgia, Chiara
AU - Karanjia, Rustum
AU - Taiel, Magali
AU - Blouin, Laure
AU - Burguière, Pierre
AU - Smits, Gerard
AU - Chevalier, Caroline
AU - Masonson, Harvey
AU - Salermo, Yordak
AU - Katz, Barrett
AU - Picaud, Serge
AU - Calkins, David J.
AU - Sahel, José Alain
N1 - Ricercatore distaccato presso IRCCS a seguito Convenzione esclusiva con Università di Bologna (Carelli Valerio, La Morgia Chiara)
PY - 2020/12/9
Y1 - 2020/12/9
N2 - REVERSE is a randomized, double-masked, sham-controlled, multicenter, phase 3 clinical trial that evaluated the efficacy of a single intravitreal injection of rAAV2/2-ND4 in subjects with visual loss from Leber hereditary optic neuropathy (LHON). A total of 37 subjects carrying the m.11778G>A (MT-ND4) mutation and with duration of vision loss between 6 to 12 months were treated. Each subject's right eye was randomly assigned in a 1:1 ratio to treatment with rAAV2/2-ND4 (GS010) or sham injection. The left eye received the treatment not allocated to the right eye. Unexpectedly, sustained visual improvement was observed in both eyes over the 96-week follow-up period. At week 96, rAAV2/2-ND4-treated eyes showed a mean improvement in best-corrected visual acuity (BCVA) of −0.308 LogMAR (+15 ETDRS letters). A mean improvement of −0.259 LogMAR (+13 ETDRS letters) was observed in the sham-treated eyes. Consequently, the primary end point, defined as the difference in the change in BCVA from baseline to week 48 between the two treatment groups, was not met (P= 0.894). At week 96, 25 subjects (68%) had a clinically relevant recovery in BCVA from baseline in at least one eye, and 29 subjects (78%) had an improvement in vision in both eyes. A nonhuman primate study was conducted to investigate this bilateral improvement. Evidence of transfer of viral vector DNA from the injected eye to the anterior segment, retina, and optic nerve of the contralateral noninjected eye supports a plausible mechanistic explanation for the unexpected bilateral improvement in visual function after unilateral injection.
AB - REVERSE is a randomized, double-masked, sham-controlled, multicenter, phase 3 clinical trial that evaluated the efficacy of a single intravitreal injection of rAAV2/2-ND4 in subjects with visual loss from Leber hereditary optic neuropathy (LHON). A total of 37 subjects carrying the m.11778G>A (MT-ND4) mutation and with duration of vision loss between 6 to 12 months were treated. Each subject's right eye was randomly assigned in a 1:1 ratio to treatment with rAAV2/2-ND4 (GS010) or sham injection. The left eye received the treatment not allocated to the right eye. Unexpectedly, sustained visual improvement was observed in both eyes over the 96-week follow-up period. At week 96, rAAV2/2-ND4-treated eyes showed a mean improvement in best-corrected visual acuity (BCVA) of −0.308 LogMAR (+15 ETDRS letters). A mean improvement of −0.259 LogMAR (+13 ETDRS letters) was observed in the sham-treated eyes. Consequently, the primary end point, defined as the difference in the change in BCVA from baseline to week 48 between the two treatment groups, was not met (P= 0.894). At week 96, 25 subjects (68%) had a clinically relevant recovery in BCVA from baseline in at least one eye, and 29 subjects (78%) had an improvement in vision in both eyes. A nonhuman primate study was conducted to investigate this bilateral improvement. Evidence of transfer of viral vector DNA from the injected eye to the anterior segment, retina, and optic nerve of the contralateral noninjected eye supports a plausible mechanistic explanation for the unexpected bilateral improvement in visual function after unilateral injection.
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U2 - 10.1126/scitranslmed.aaz7423
DO - 10.1126/scitranslmed.aaz7423
M3 - Article
C2 - 33298565
AN - SCOPUS:85095991918
VL - 12
JO - Science Translational Medicine
JF - Science Translational Medicine
SN - 1946-6234
IS - 573
M1 - eaaz7423
ER -