Inherited Retinal Diseases and Gene Therapy Group

P.I.;Yusuke Murakami

Toward development of new therapies against intractable retinal dystrophies

Inherited retinal diseases (IRDs) are currently incurable disorders with which more than 200 causal genes are associated. Our team aims to elucidate the genotype-phenotype relationships in IRDs as well as to clarify the mechanisms of retinal degeneration, thereby delivering new tools and medicine (e.g. gene therapy, nano-particle medicine, and novel compounds) to IRDs patients with a significant unmet needs. One major interest of our lab is the mechanisms of cell death and neuroinflammation in retinitis pigmentosa (RP), a form of IRDs with rod-cone dystrophy. For example, we have recently identified that circulating blood inflammatory monocytes contribute to the progression of RP, and we are now developing nano-particle medicine that attenuates inflammatory monocytes and peripherally engrafted macrophages (Fig. 1).

Based on our basic and clinical studies, we are now conducting Phase 1/2a clinical trial of neuroprotective gene therapy for patients with RP. In this trial, lentiviral vector encoding pigment epithelium-derived factor (PEDF) is injected into the subretinal space for the purpose of delaying the disease progression (Fig. 2). We are also developing gene therapy agents against other IRDs that are frequent in Asian populations.

Selected publications

1. Circulating inflammatory monocytes oppose microglia and contribute to cone cell death in retinitis pigmentosa.
   Funatsu J, Murakami Y, Shimokawa S, Nakatake S, Fujiwara K, Okita A, Fukushima M, Shibata K, Yoshida N, Koyanagi Y, Akiyama M, Notomi S, Nakao S, Hisatomi T, Takeda A, Paschalis EI, Vavvas DG, Ikeda Y, Sonoda KH.
   PNAS Nexus. 2022 ; 1: pgac003.
2. Genotype and Long-term Clinical Course of Bietti Crystalline Dystrophy in Korean and Japanese Patients.
   Murakami Y, Koyanagi Y, Fukushima M, Yoshimura M, Fujiwara K, Akiyama M, Momozawa Y, Ueno S, Terasaki H, Oishi A, Miyata M, Ikeda H, Tsujikawa A, Mizobuchi K, Hayashi T, Fujinami K, Tsunoda K, Park JY, Han J, Kim M, Lee CS, Kim SJ, Park TK, Joo K, Woo SJ, Ikeda Y, Sonoda KH.
   Ophthalmol Retina. 2021; S2468-6530.
3. Changes of Serum Inflammatory Molecules and Their Relationships with Visual Function in Retinitis Pigmentosa
   Okita A, Murakami Y, Shimokawa S, Funatsu J, Fujiwara K, Nakatake S, Koyanagi Y, Akiyama M, Takeda A, Hisatomi T, Ikeda Y, Sonoda KH;
   Invest Ophthalmol Vis Sci. 61(11):30, 2020/09/01
4. Aqueous Flare and Progression of Visual Field Loss in Patients With Retinitis Pigmentosa
   Kohta Fujiwara , Yasuhiro Ikeda , Yusuke Murakami , Takashi Tachibana , Jun Funatsu , Yoshito Koyanagi , Shunji Nakatake , Shotaro Shimokawa , Noriko Yoshida , Shintaro Nakao , Toshio Hisatomi , Tatsuro Ishibashi , Koh-Hei Sonoda Invest Ophthalmol Vis Sci. 61(8):26.2020/7/1
5. Innate immune response in retinal homeostasis and inflammatory disorders.
   Murakami Y, Ishikawa K, Nakao S, Sonoda KH.
   Prog Retin Eye Res. 2020 Jan;74:100778
6. Genetic characteristics of retinitis pigmentosa in 1204 Japanese patients.
   Koyanagi Y, Akiyama M, Nishiguchi KM, Momozawa Y, Kamatani Y, Takata S, Inai C, Iwasaki Y, Kumano M, Murakami Y, Omodaka K, Abe T, Komori S, Gao D, Hirakata T, Kurata K, Hosono K, Ueno S, Hotta Y, Murakami A, Terasaki H, Wada Y, Nakazawa T, Ishibashi T, Ikeda Y, Kubo M, Sonoda KH.
   J Med Genet. 2019 Oct;56(10):662-670.
7. MUTYH promotes oxidative microglial activation and inherited retinal degeneration. Nakatake S, Murakami Y, Ikeda Y, Morioka N, Tachibana T, Fujiwara K, Yoshida N, Notomi S, Hisatomi T, Yoshida S, Ishibashi T, Nakabeppu Y, Sonoda KH.
   JCI Insight. 2016 Sep 22;1(15):e87781.
8. Clinical evidence of sustained chronic inflammatory reaction in Retinitis Pigmentosa.
   Yoshida N, Ikeda Y, Notomi S, Ishikawa K, Murakami Y, Hisatomi T, Enaida H, Ishibashi T.
   Ophthalmology. 2013 Jan;120(1):100-5.
9. Stable Retinal Gene Expression in Nonhuman Primates via Subretinal Injection of SIVagm-based Lentiviral Vectors.
   Ikeda Y, Yonemitsu Y, Miyazaki M, Kohno R, Murakami Y, Murata T, Tabata T, Ueda Y, Ono F, Suzuki T, Ageyama N, Terao K, Hasegawa M, Sueishi K, Ishibashi T.
   Hum Gene Ther. 2009 Jun;20(6):573-9.
10. Simian lentiviral vector-mediated retinal gene transfer of pigment epithelium-derived factor protects retinal degeneration and electrical defect in Royal College of Surgeons rats.
    Miyazaki M, Ikeda Y, Yonemitsu Y, Goto Y, Sakamoto T, Tabata T, Ueda Y, Hasegawa M, Tobimatsu S, Ishibashi T, Sueishi K.
    Gene Ther. 2003 Aug;10(17):1503-11.