Gene Therapy in X-linked Retinitis Pigmentosa Due to Defects in RPGR

Abstract

Retinitis pigmentosa GTPase regulator (RPGR) gene sequence variants account for most of X-linked retinitis pigmentosa (XLRP). Symptoms such as nyctalopia typically begin in childhood, with increasing loss of peripheral visual field during teenage years, and progressive loss of central vision later in the disease process. RPGR is involved in ciliary function, with ciliary dysfunction now recognised as the mechanism underlying a large proportion of inherited retinal disease. There has been significant progress in identifying animal models to define the underlying disease mechanisms and to test gene replacement therapy. This progress, combined with advances in human retinal imaging, have culminated in multiple on-going gene therapy clinical trials. This review summarizes the molecular genetics, protein function, clinical phenotypes, animal models and the clinical trials for RPGR-associated RP.

Novel hemizygous single‐nucleotide duplication in RPGR in a patient with retinal dystrophy and sensorineural hearing loss

“…Pathogenic variants in RPGR have been reported to cause nearly two‐thirds of all X‐linked retinitis pigmentosa (Khanna et al., 2005 ; Mihailovic et al., 2022 ; Vervoort et al., 2000 ). Individuals with RPGR ‐related X‐linked retinitis pigmentosa (XLRP) have an aggressive form of the disease, characterized by night blindness in the first or second decades of life, followed by progressive loss of visual acuity and legal blindness by the third or fourth decades of life (Di Iorio et al., 2020 ; Georgiou et al., 2021 ; Nguyen et al., 2020 ; Sandberg et al., 2007 ). Individuals with RPGR ‐related retinal diseases can also manifest extraocular phenotypes, including hearing loss, chronic otitis media, sinusitis, bronchitis, and bronchiectasis (Georgiou et al., 2021 ; Zito et al., 2003 ).…”

“…Due to X‐linked inheritance, most affected individuals are hemizygous males. However, heterozygous female carriers can also have ocular findings which can range from minimal visual impairment to severe retinitis pigmentosa (RP), sometimes with extraocular findings, particularly sinusitis, otitis media, and hearing loss (Georgiou et al., 2021 ; Tuupanen et al., 2022 ; Zito et al., 2003 ).…”

Genetic Characteristics and Long-Term Follow-Up of Slovenian Patients with RPGR Retinal Dystrophy

“…Most RPGR patients have myopia; this includes those with RP and those with the COD/CORD phenotype [ 21 ]. A correlation between a high myopic refractive error and faster rates of VA loss in all phenotypes has been reported, but this remains debatable [ 33 ].…”

Microperimetry as an Outcome Measure in RPGR-associated Retinitis Pigmentosa Clinical Trials

“… 1 Currently, there is no treatment for RPGR -associated RP, but gene therapy clinical trials have been underway for the last 5 years. 2 , 3 RPGR -associated RP typically (although not always) presents as a rod-cone dystrophy and is characterized by early onset nyctalopia, followed by progressive peripheral visual field loss. Visual acuity (VA) is moderately preserved until the retinal degeneration encroaches centrally, occurring around the fourth decade and resulting in severe sight impairment.…”