TY - JOUR
T1 - Choroideremia Gene Therapy Phase 2 Clinical Trial
T2 - 24-Month Results
AU - Lam, Byron L.
AU - Davis, Janet L.
AU - Gregori, Ninel Z.
AU - MacLaren, Robert E.
AU - Girach, Aniz
AU - Verriotto, Jennifer D.
AU - Rodriguez, Belen
AU - Rosa, Potyra R.
AU - Zhang, Xiaojun
AU - Feuer, William J.
N1 - Funding Information:
Funding/Support: James V. Bastek, M.D. Hereditary Retinal Disease Research Program and the Hope for Vision Arsht Fund , Bascom Palmer Eye Institute , University of Miami Miller School of Medicine provided funding for the conduct of the study, including purchase of investigational product (AAV2-REP1; NSR-REP1) from Nightstar Therapeutics. Financial Disclosures: Byron L. Lam: National Eye Institute (grants: R01EY026643-01A1 , R01EY023666 , U10 EY023558-01A1 ); AGTC, Astellas, Editas, Envision, Nightstar, Quark, Sanofi, Second Sight Medical Products (study grants); Ionis, Shire, Spark (consultant), Allergan (data safety monitoring committee). Janet L. Davis: Nightstar (study grant), Abbvie (data safety monitoring committee, consultant). Ninel Z. Gregori: Nightstar (study grant). Robert E. MacLaren: Nightstar (consultant, equity, study grant), Spark (consultant). Aniz Girach: Nightstar (former employee). William J. Feuer: National Eye Institute (grants: U10EY024247 , P30EY014801 ); Johnson and Johnson (study grant); Glaucoma Associates of Texas, Retinal Care LLC, Tissue Tech (consultant). The following authors have no financial disclosures: Jennifer D. Verriotto, Belen Rodriguez, Potyra R. Rosa, and Xiaojun Zhang. All authors attest that they meet the current ICMJE criteria for authorship.
Funding Information:
Funding/Support: James V. Bastek, M.D. Hereditary Retinal Disease Research Program and the Hope for Vision Arsht Fund, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine provided funding for the conduct of the study, including purchase of investigational product (AAV2-REP1; NSR-REP1) from Nightstar Therapeutics. Financial Disclosures: Byron L. Lam: National Eye Institute (grants: R01EY026643-01A1, R01EY023666, U10 EY023558-01A1); AGTC, Astellas, Editas, Envision, Nightstar, Quark, Sanofi, Second Sight Medical Products (study grants); Ionis, Shire, Spark (consultant), Allergan (data safety monitoring committee). Janet L. Davis: Nightstar (study grant), Abbvie (data safety monitoring committee, consultant). Ninel Z. Gregori: Nightstar (study grant). Robert E. MacLaren: Nightstar (consultant, equity, study grant), Spark (consultant). Aniz Girach: Nightstar (former employee). William J. Feuer: National Eye Institute (grants: U10EY024247, P30EY014801); Johnson and Johnson (study grant); Glaucoma Associates of Texas, Retinal Care LLC, Tissue Tech (consultant). The following authors have no financial disclosures: Jennifer D. Verriotto, Belen Rodriguez, Potyra R. Rosa, and Xiaojun Zhang. All authors attest that they meet the current ICMJE criteria for authorship.
Publisher Copyright:
© 2018 Elsevier Inc.
PY - 2019/1
Y1 - 2019/1
N2 - Purpose: To report the final results of a phase 2 high-dose gene therapy clinical trial in choroideremia. Methods: Design: Phase 2 clinical trial. Participants: Six men (aged 32-72 years) with genetically-confirmed advanced choroideremia. Patients received subfoveal injection of AAV2-REP1 (1011 genome particles in 0.1 mL) in the worse-sighted eye. Outcome Measures: Primary measure was best-corrected visual acuity (BCVA) change from baseline in the treated eye compared to the untreated eye. Secondary endpoints included change from baseline in microperimetry, fundus autofluorescence, and spectral-domain optical coherence tomography (OCT). Safety evaluations included adverse events, viral shedding in body fluids, and vector antibody responses. Results: Baseline mean ETDRS BCVA was 65.3 ± 8.8 (SD, range 56-77, 20/32-20/80) letters in the treated eyes and 77.0 ± 4.2 (69-81, 20/25-20/40) letters in the untreated eyes. At 2 years, 1 treated eye improved by 10 letters and another by 5 letters, while 1 untreated eye improved by 4 letters. All other eyes were within 2 letters of baseline. Baseline microperimetry sensitivities in the treated eyes were poor (1.2 ± 2.1 (0, 5.1) dB) and showed no significant change. No serious adverse event occurred. Two patients developed an atrophic retinal hole in a nonfunctioning macular area where baseline OCT showed preexisting thinning. Intraoperative microscope-integrated OCT allowed proper subretinal injection with avoidance of excessive foveal stretching and macular hole formation. Conclusions: Sustained improvement or maintenance of BCVA is achievable in choroideremia with high-dose AAV2-REP1, indicating BCVA is a viable primary outcome in advanced choroideremia. Choroideremia gene therapy delivered with intraoperative OCT has a good safety profile.
AB - Purpose: To report the final results of a phase 2 high-dose gene therapy clinical trial in choroideremia. Methods: Design: Phase 2 clinical trial. Participants: Six men (aged 32-72 years) with genetically-confirmed advanced choroideremia. Patients received subfoveal injection of AAV2-REP1 (1011 genome particles in 0.1 mL) in the worse-sighted eye. Outcome Measures: Primary measure was best-corrected visual acuity (BCVA) change from baseline in the treated eye compared to the untreated eye. Secondary endpoints included change from baseline in microperimetry, fundus autofluorescence, and spectral-domain optical coherence tomography (OCT). Safety evaluations included adverse events, viral shedding in body fluids, and vector antibody responses. Results: Baseline mean ETDRS BCVA was 65.3 ± 8.8 (SD, range 56-77, 20/32-20/80) letters in the treated eyes and 77.0 ± 4.2 (69-81, 20/25-20/40) letters in the untreated eyes. At 2 years, 1 treated eye improved by 10 letters and another by 5 letters, while 1 untreated eye improved by 4 letters. All other eyes were within 2 letters of baseline. Baseline microperimetry sensitivities in the treated eyes were poor (1.2 ± 2.1 (0, 5.1) dB) and showed no significant change. No serious adverse event occurred. Two patients developed an atrophic retinal hole in a nonfunctioning macular area where baseline OCT showed preexisting thinning. Intraoperative microscope-integrated OCT allowed proper subretinal injection with avoidance of excessive foveal stretching and macular hole formation. Conclusions: Sustained improvement or maintenance of BCVA is achievable in choroideremia with high-dose AAV2-REP1, indicating BCVA is a viable primary outcome in advanced choroideremia. Choroideremia gene therapy delivered with intraoperative OCT has a good safety profile.
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U2 - 10.1016/j.ajo.2018.09.012
DO - 10.1016/j.ajo.2018.09.012
M3 - Article
C2 - 30240725
AN - SCOPUS:85055757007
VL - 197
SP - 65
EP - 73
JO - American Journal of Ophthalmology
JF - American Journal of Ophthalmology
SN - 0002-9394
ER -