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Abstract Details

Ocular Post-mortem Analyses with Histopathological and Molecular Assessments in Leber Hereditary Optic Neuropathy Following AAV2 Gene Therapy
Neuro-ophthalmology/Neuro-otology
P5 - Poster Session 5 (8:00 AM-9:00 AM)
11-025

To report post-mortem ocular analyses in two patients with Leber hereditary optic neuropathy (LHON) who received lenadogene nolparvovec (LN) gene therapy.

LN is an AAV2-based gene therapy for LHON patients carrying the m.11778G>A MT-ND4 mutation. All LN gene therapy trials have demonstrated a bilateral effect after unilateral intravitreal injection.
Two patients with MT-ND4-LHON received an intravitreal injection of LN in one eye and a sham injection in the other within 6 months after bilateral vision loss. Post-mortem histopathological and molecular (ddPCR) analyses were performed on laser-captured retinal and optic nerve samples.
Within 2 months of gene therapy, both participants developed intraocular inflammation in the treated eye; both events resolved within months. Patient 1 died of acute alcohol toxicity and patient 2 of cardiac arrest. Patient 1 had severe optic atrophy and loss of retinal ganglion cells (RGCs), while patient 2 was a milder case of LHON, with consistent preservation of RGCs and optic nerve axons, with only the temporal fibers lost. In patient 1, an angiocentric lymphocytic chronic inflammation was noted in the optic nerve head and temporal retina. No persistent inflammation was seen in patient 2. AAV2-ND4 distribution in the treated eye was asymmetric in both patients, more prevalent in temporal RGCs. A much lower level of AAV2-ND4 was detected in the retina of the untreated eye in both cases. MtDNA copy number was upregulated in both eyes of patient 2, possibly reflecting better preservation of RGCs and axons.
This is the first postmortem study of human eyes injected unilaterally with AAV2-based gene therapy. Gene transfection of RGCs was successful in both eyes despite unilateral administration. AAV2-ND4 transfer seems to be facilitated by axonal preservation, to be confirmed and further characterized by additional analyses of the eyes, nerves, optic chiasm and optic tracts from patient 2.
Authors/Disclosures
Valerie Biousse, MD
PRESENTER 		Dr. Biousse has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Gensights Biologic. Dr. Biousse has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Topcon. Dr. Biousse has received publishing royalties from a publication relating to health care. Dr. Biousse has received publishing royalties from a publication relating to health care.
Valerio Carelli, MD, PhD (University of Bologna) Dr. Carelli has received personal compensation in the range of $0-$499 for serving as a Consultant for Chiesi Farmaceutici. Dr. Carelli has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Chiesi Farmaceutici.
Nancy J. Newman, MD, FAAN (Emory University School of Medicine) Dr. Newman has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for GenSight. Dr. Newman has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Chiesi. Dr. Newman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Stoke. Dr. Newman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eli Lilly. Dr. Newman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Phelcom. The institution of Dr. Newman has received research support from GenSight. Dr. Newman has received publishing royalties from a publication relating to health care. Dr. Newman has received publishing royalties from a publication relating to health care. Dr. Newman has received publishing royalties from a publication relating to health care.
Leonardo Caporali, PhD Dr. Caporali has nothing to disclose.
Fred N. ROSS-CISNEROS, BA Mr. ROSS-CISNEROS has nothing to disclose.
Elisa Boschetti Dr. Boschetti has nothing to disclose.
Lindreth G. DuBois, MEd, MMSc Ms. DuBois has received publishing royalties from a publication relating to health care.
Henry Liu Mr. Liu has nothing to disclose.
Philippe Ancian, PhD Dr. Ancian has nothing to disclose.
Magali Taiel Magali Taiel has received personal compensation for serving as an employee of GenSight Biologics.
Alfredo Sadun, MD (Doheny Eye Institute USC Sch.) Dr. Sadun has received publishing royalties from a publication relating to health care.