SUMMARY  

• Botaretigene sparoparvovec is an investigational adeno-associated virus vector type 5 (AAV5) gene therapy being studied for the treatment of X-linked retinitis pigmentosa (XLRP) associated with disease causing sequence variants in the retinitis pigmentosa GTPase regulator (RPGR) gene.^1,2
• The AAV5 capsid contains a linear single strand of human RPGR-ORF15 deoxyribonucleic acid (DNA) with an in frame deletion in the purine-rich tract in the ORF15 region. The transgene is driven by human rhodopsin kinase promoter (hRKp) to drive expression.²

BACKGROUND

Retinitis pigmentosa (RP), a leading form of inherited blindness, has multiple forms of inheritance (autosomal dominant, autosomal recessive, and X-linked). The most common form of XLRP is caused by mutations in the RPGR gene, accounting for over 70% of XLRP cases and 20% of all RP cases.^3,4 The ORF15 variant of RPGR is expressed predominantly in photoreceptors and is needed for normal rod and cone function in the retina.³ The ORF15 region on the RPGR gene contains a long, purine-rich, and repetitive sequence, with 60% of XLRP patients having mutations identified in this area.⁴

Mechanism of action

Botaretigene sparoparvovec is an investigational AAV5 gene therapy being studied for the treatment of XLRP associated with disease causing sequence variants in the RPGR gene. An AAV5 capsid encases a linear single strand of human RPGR-ORF15 DNA and delivers the truncated RPGR-ORF15 transgene and the hRKp (restricts expression of transgene to photoceptor cells) to rod and cone photoreceptors. The transgene is flanked by inverted terminal repeats of AAV serotype 2. The truncated human RPGR-ORF15 sequence contains a 378 base pair in frame deletion in the highly repetitive purine-rich region to stabilize the transgene while still resulting in expression of functional protein. Replacement gene therapy with RPGR-ORF15 is sufficient to rescue photoreceptor degeneration in RPGR-deficient mice.^2,3,5

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 08 July 2024.