Acute toxicity study of a simian immunodeficiency virus-based lentiviral vector for retinal gene transfer in nonhuman primates.
A phase 1 clinical trial evaluating the safety of gene therapy for patients with wet age-related macular degeneration (AMD) or retinoblastoma has been completed without problems. The efficacy of gene therapy for Leber's congenital amaurosis (LCA) was reported by three groups. Gene therapy may thus hold promise as a therapeutic method for the treatment of intractable ocular diseases. However, it will first be important to precisely evaluate the efficiency and safety of alternative gene transfer vectors in a preclinical study using large animals. In the present study, we evaluated the acute local (ophthalmic) and systemic toxicity of our simian immunodeficiency virus from African green monkeys (SIVagm)-based lentiviral vectors carrying human pigment epithelium-derived factor (SIV-hPEDF) for transferring genes into nonhuman primate retinas. Transient inflammation and elevation of intraocular pressure were observed in some animals, but these effects were not dose dependent. Electroretinograms (ERGs), including multifocal ERGs, revealed no remarkable change in retinal function. Histopathologically, SIV-hPEDF administration resulted in a certain degree of inflammatory reaction and no apparent structural destruction in retinal tissue. Regarding systemic toxicity, none of the animals died, and none showed any serious side effects during the experimental course. No vector leakage was detected in serum or urine samples. We thus propose that SIVagm-mediated stable gene transfer might be useful and safe for ocular gene transfer in a clinical setting.
Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan. ymocl@pathol1.med.kyushu-u.ac.jp
Yasuhiro
Y
Ikeda
Yoshikazu
Y
Yonemitsu
Masanori
M
Miyazaki
Ri-ichiro
R
Kohno
Yusuke
Y
Murakami
Toshinori
T
Murata
Yoshinobu
Y
Goto
Toshiaki
T
Tabata
Yasuji
Y
Ueda
Fumiko
F
Ono
Toshimichi
T
Suzuki
Naohide
N
Ageyama
Keiji
K
Terao
Mamoru
M
Hasegawa
Katsuo
K
Sueishi
Tatsuro
T
Ishibashi
D000818:Animals; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D004596:Electroretinography; D005136:Eye Proteins / Q000235:genetics*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000009:adverse effects*; D049452:Green Fluorescent Proteins; D006801:Humans; D008252:Macaca fascicularis; D023421:Models, Animal; D009414:Nerve Growth Factors / Q000235:genetics*; D012160:Retina / Q000473:pathology / Q000821:virology*; D015843:Serpins / Q000235:genetics*; D015302:Simian Immunodeficiency Virus / Q000235:genetics*; D014161:Transduction, Genetic; D019076:Transgenes; D016896:Treatment Outcome; D000099174:Pigment Epithelium-Derived Factor
D005136:Eye Proteins; D049452:Green Fluorescent Proteins; D009414:Nerve Growth Factors; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor; C485184:enhanced green fluorescent protein