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Advances in RPGR gene therapy for X‑linked retinitis pigmentosa: From preclinical insights to clinical application (Review)

  • Authors:
    • Yushan Long
    • Jia Qi
    • Wenliang Zhang
    • Huan Qin
    • Kai Yao
  • View Affiliations / Copyright

    Affiliations: Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology, Wuhan, Hubei 430065, P.R. China
    Copyright: © Long et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].
  • Article Number: 52
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    Published online on: December 30, 2025
       https://doi.org/10.3892/ijmm.2025.5723
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Abstract

X‑linked retinitis pigmentosa, primarily caused by mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene, represents one of the most severe forms of inherited retinal degeneration, with early onset and rapid progression. Conventional interventions, such as vitamin A or docosahexaenoic acid supplementation, offer limited benefits and fail to halt disease progression. By contrast, gene therapy has emerged as a promising approach to alter the disease course. The present review summarizes the clinical phenotypes and pathogenic mechanisms associated with RPGR mutations, focusing on their disruption of ciliary transport and metabolic homeostasis. The present review further discusses advances in preclinical models, including mice, dogs, zebrafish and induced pluripotent stem cell‑derived organoids, that have facilitated the development of RPGR‑targeted therapies. Adeno‑associated virus‑based gene replacement has shown efficacy in restoring retinal structure and function, and several approaches have progressed to early‑phase clinical trials. Despite encouraging outcomes, challenges such as RPGR coding sequence instability, vector delivery efficiency and long‑term safety remain. The present review integrates current mechanistic understanding and therapeutic progress, providing a translational perspective for precision treatment of RPGR‑associated retinal diseases.
View Figures

Figure 1

Patterns of inheritance and
characteristics of disease progression in RP. (A) RP mode of
inheritance. (B) Genes causing XLRP. (C) Proportion of male to
female patients. (D) Classification of RPGR-associated
diseases. (E) Disease course and (F) clinical manifestations. Early
stage: Night blindness and reduced light sensitivity; middle stage:
Central vision and peripheral VF defects; late stage:
bone-spicule-like pigmentation and macular atrophy. Comparison of
the diseased retina with the normal retina shows pathological
features such as vascular narrowing of the blood vessels and
pigmentation abnormalities. RP, retinitis pigmentosa; XLRP,
X-linked retinitis pigmentosa; RPGR, retinitis pigmentosa
GTPase regulator; VF, visual field.

Figure 2

Information on the structure and
mutation of RPGR genes in different species. Structure of
the RPGR gene in (A) human, (B) mice, (C) canines and (D)
zebrafish, including exon-intron composition, number of base pairs
and amino acid length of the different transcripts. (E) Common
mutations in RCC1-like domains. (F) Pathogenic processes resulting
from mutations in the two transcripts leading to age-dependent
phenotypic changes. The horizontal axis represents age, and the
vertical axis reflects the severity of ocular symptoms. From left
to right, the symptoms progress from night blindness to central
vision loss, VF defects, and eventually legal blindness,
illustrating the trajectory of disease development under different
transcript mutations. (G) Role of the two transcripts in the
organism. RPGR gene, retinitis pigmentosa GTPase
regulator gene; VF, visual field.

Figure 3

Structure of the eye and the role of
RPGR in photoreceptors. (A) Layered structure of the eye and
retina. (B) Retinal layers organized into three functional domains:
The support layer (BrM; RPE), the light-signal-processing layer
(OS, IS and ONL) and the neurointegrative layer (OPL, INL, IPL, GCL
and NFL). (C) Photoreceptor subcellular structures and the '9+0'
signaling axis, representing the microtubule arrangement pattern
unique to non-motile cilia. (D) Mechanisms of internal ciliary
transport involving the RPGR complex. IFT: KIF3A and Dynein mediate
bi-directional cargo transport. RAB8A participates in vesicle
transport and regulates photoreceptor OS disc membrane renewal.
Mechanisms involving RPGR, RAB8A and RAB37 in vision-related
physiological processes. RPGR participates in the transport
processes involving RAB8A and RAB37. These GTPases exert their
functions through cycling between GTP-bound and GDP-bound states.
RAB8A is involved in the correct localization of RHO to CC, thereby
maintaining normal vision. RAB37 facilitates the conversion of
LC3B-I to LC3B-II to support normal autophagy, which in turn helps
maintain vision. Key regulatory proteins: RPGR (green), RPGRIP1
(orange), NPHP4 (earthy yellow), RAB8A (bright yellow), GTP (red),
GDP (light red), RHO (purple), CC (blue), RAB37 (blue), LC3B-I
(light blue), LC3B-II (dark blue). BrM, Bruch's membrane; RPE,
retinal pigment epithelium; OS, outer segment; ONL, outer nuclear
layer; OPL, outer plexiform layer; INL, inner nuclear layer; IPL,
inner plexiform layer; GCL, ganglion cell layer; NFL, nerve fiber
layer. RPGR, retinitis pigmentosa GTPase regulator; RHO, Rhodopsin;
RPGRIP1L, RPGRIP1-like protein; RPGRIP1, RPGR-interacting protein
1; RAB8A, RAS-related protein Rab-8A; IFT, intraflagellar
transport; KIF3A, kinesin family member 3A; NPHP4, nephrocystin 4;
CC, connecting cilium; LC3B-I, microtubule-associated protein 1
light chain 3 β-I; LC3B-II, microtubule-associated protein 1 light
chain 3 β-II.

Figure 4

Interaction network of RPGR proteins
and their functional mechanism in cilium. (A) Structural domain
characterization of RPGR protein isoforms, where blue dots indicate
sites of frameshift mutations. RPGRex1-19
contains exons 1-10, 11-14 and 16-19; its N terminus includes the
RLD, and its C terminus contains several regions of unknown
function. RPGRORF15 consists of exons 1-10, 11-14
and ORF15; it contains an acidic, glutamate-rich domain (EG-rich
domain) and a basic domain. (B) Interacting protein networks of
RPGR. Proteins directly binding to the RLDs: RPGRIP1, RPGRIP1L,
RAB8A and PDE6D. Complex-associated proteins:
Cilium-transport-related proteins (CEP290, IFT88, KIF3A, RAB11 and
γ-Tubulin); signaling-regulation-related [NPHP family proteins
(NPHP1/4/5), TTLL5, ARL2/3]; and structure-maintenance-related
(SMC1/3, SPATA7). (C) Functional pathways of RPGR in ciliary
signaling. RPGR is involved in the regulation of
phosphatidylinositol metabolism. INPP5E is isoprenylated through
its C-terminal CAAX motif and binds PDE6D to form a complex, which
ensures its proper membrane localization. ARL3 promotes the release
of PDE6D in the activated state. ARL3, in its activated state,
promotes the release of INPP5E from PDE6D and the dissociated
INPP5E is translocated to the ciliary membrane via the IFT
mechanism. ARL13B ensures the stable localization of INPP5E to the
ciliary membrane by binding to INPP5E. RPGR, retinitis pigmentosa
GTPase regulator; RLDs, RCC1-like domains; RPGRIP1,
RPGR-interacting protein 1; RPGRIP1L, RPGRIP1-like protein; RAB8A,
RAS-related protein Rab-8A; PDE6D, Phosphodiesterase 6 δ subunit,
CEP290, Centrosomal Protein 290; IFT88, Intraflagellar Transport
88; KIF3A, Kinesin Family Member 3A; RAB11, Ras-Related Protein
Rab-11; NPHP1, Nephrocystin 1; NPHP4, Nephrocystin 4; NPHP 5,
Nephrocystin 5; TTLL5, Tubulin tyrosine ligase-like family member
5; ARL2, ADP-Ribosylation Factor-Like Protein 2; ARL3,
ADP-Ribosylation Factor-Like Protein 3; ARL13B, ADP-Ribosylation
Factor-Like Protein 13B; SMC1, Structural maintenance of
chromosomes protein 1; SMC3, Structural maintenance of chromosomes
protein 3; SPATA7, Spermatogenesis-Associated Protein 7; INPP5E,
Inositol polyphosphate-5-phosphatase E.

Figure 5

Impact of RPGR-associated
phosphoinositide signaling on cellular energy homeostasis. (A)
Normal metabolic conditions. In retinal cells under normal
metabolic conditions, mTORC1 is activated in the presence of
sufficient energy, promoting mitochondrial activity to sustain
cellular survival. Additionally, mTORC1 activates S6K and 4E-BP1,
thereby enhancing protein synthesis. Conversely, during energy
depletion, AMPK inhibits mTORC1, reducing metabolic activity while
simultaneously activating autophagy to provide an alternative
energy source for the cell. (B) Pathological metabolic conditions.
In pathological retinal cells, excessive activation of mTORC1
occurs when energy is abundant. Under these conditions, mTORC1
suppresses the AMPK pathway, leading to decreased autophagy and an
inability to efficiently clear intracellular waste. AMPK activity
also contributes to increased ROS levels. Meanwhile, the heightened
metabolic demand results in energy exhaustion, further triggering
ROS activation, excessive intracellular waste accumulation and
oxidative stress. By contrast, severe energy deprivation leads to
excessive inhibition of mTORC1, which blocks the activation of S6K
and 4E-BP1, thereby suppressing protein and lipid synthesis and
disrupting normal cellular metabolism. This energy-deficient state
also activates the AMPK pathway, increasing intracellular
autophagy. (C) RPGR may regulate photoreceptor degeneration through
multiple signaling pathways. Solid lines indicate pathways
supported by existing studies, such as PI3K/AKT/mTORC1 and AMPK in
autophagy regulation; dashed lines represent hypothetical
mechanisms suggesting potential involvement of MAPK and metabolic
stress pathways. (D) RPGR dysfunction leads to structural and
functional degeneration of photoreceptors. Key mechanisms include
transport defects, metabolic imbalance, oxidative stress and
activation of apoptotic pathways. (E) Indirect role of RPGR in
phosphoinositide metabolism. mTOR, in complex with mTORC1, serves
as a central regulator influenced by multiple factors, including
AMPK, the TSC1-TSC2 complex and AKT. These pathways collectively
modulate protein and lipid synthesis as well as autophagy. In
phosphoinositide metabolism, AKT is activated via the
PI3K-PIP3 pathway, while PTEN dephosphorylates
PIP3 to maintain homeostasis. PTEN dysfunction leads to
excessive PIP3 accumulation. TTLL5 facilitates the
proper glutamylation of RPGR, enabling INPP5E to function correctly
within the phosphoinositide pathway, thereby indirectly regulating
the mTOR pathway and sustaining normal cellular growth and
metabolism. mTOR, mechanistic Target of Rapamycin; mTORC1, mTOR
Complex 1; S6K, Ribosomal protein S6 kinase; 4E-BP1, Eukaryotic
Translation Initiation Factor 4E-Binding Protein 1; AMPK,
AMP-activated protein kinase signaling pathway; ROS, Reactive
oxygen species; PI3K/AKT, Phosphoinositide 3-kinase/AKT signaling
pathway; MAPK, Mitogen-activated protein kinase signaling pathway;
PI3K-PIP3, Phosphoinositide
3-kinase–phosphatidylinositol (3,4,5)-trisphosphate signaling pathway;
PTEN, Phosphatase and tensin homolog; TTLL5, Tubulin tyrosine
ligase-like family member 5; INPP5E, Inositol
polyphosphate-5-phosphatase E; TSC1, Tuberous sclerosis complex 1;
TSC2, Tuberous sclerosis complex 2.

Figure 6

RPGR mutant model and gene
editing cell therapy. (A) Animal and cell models of RPGR
mutations. (B) AAV vectors and delivery methods applied in clinical
studies targeting four reported RPGR mutations. (C) Entry of
AAV vectors into the eye of a patient, followed by transduction and
subsequent RPGR protein expression. (D) Effects of subretinal
injection of RPGR gene therapy vector on retinal photoreceptor
cells. Before injection: Rods and cones show extensive
degeneration. After injection: Previously damaged rods and cones
were partially preserved via subretinal injection delivery of the
therapeutic vector. RPGR gene, retinitis pigmentosa
GTPase regulator gene; AAV, adeno-associated virus.

Figure 7

Strategies for integrated management
of ocular diseases in patients with mutated RPGR. The
program encompasses interventions (medications, nutrition and
lifestyle modifications), diagnostic tests (such as ERG),
therapeutic strategies (genetic and cellular treatments) and
preventive screening measures. (A) Interventions: Commonly used
medications, vitamin A supplementation, ophthalmic solutions, glare
avoidance and DHA intake. (B) Diagnostic assessments: ERG, BCVA, VA
and VF testing. (C) Therapeutic approaches: Treatment modalities
encompass CRISPR-Cas9-based gene editing (NHEJ and HDR), cell
transplantation (iPSCs, MSCs and ESCs), artificial vision
technologies and neurotrophic factor therapy (GDNF and BDNF). (D)
Preventive measures: Detection of pathogenic variants through NGS
and nanopore sequencing. DHA, docosahexaenoic acid; ERG,
electroretinography; BCVA, best-corrected visual acuity; VA, visual
acuity; VF, visual field; NHEJ, Non-Homologous End Joining; HDR,
Homology-Directed Repair; iPSCs, induced pluripotent stem cells;
MSCs, mesenchymal stem cells; ESCs, embryonic stem cells; GDNF,
Glial cell line-derived neurotrophic factor; BDNF, Brain-derived
neurotrophic factor; NGS, next-generation sequencing.
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Copy and paste a formatted citation
Spandidos Publications style
Long Y, Qi J, Zhang W, Qin H and Yao K: Advances in RPGR gene therapy for X‑linked retinitis pigmentosa: From preclinical insights to clinical application (Review). Int J Mol Med 57: 52, 2026.
APA
Long, Y., Qi, J., Zhang, W., Qin, H., & Yao, K. (2026). Advances in RPGR gene therapy for X‑linked retinitis pigmentosa: From preclinical insights to clinical application (Review). International Journal of Molecular Medicine, 57, 52. https://doi.org/10.3892/ijmm.2025.5723
MLA
Long, Y., Qi, J., Zhang, W., Qin, H., Yao, K."Advances in RPGR gene therapy for X‑linked retinitis pigmentosa: From preclinical insights to clinical application (Review)". International Journal of Molecular Medicine 57.3 (2026): 52.
Chicago
Long, Y., Qi, J., Zhang, W., Qin, H., Yao, K."Advances in RPGR gene therapy for X‑linked retinitis pigmentosa: From preclinical insights to clinical application (Review)". International Journal of Molecular Medicine 57, no. 3 (2026): 52. https://doi.org/10.3892/ijmm.2025.5723
Copy and paste a formatted citation
x
Spandidos Publications style
Long Y, Qi J, Zhang W, Qin H and Yao K: Advances in RPGR gene therapy for X‑linked retinitis pigmentosa: From preclinical insights to clinical application (Review). Int J Mol Med 57: 52, 2026.
APA
Long, Y., Qi, J., Zhang, W., Qin, H., & Yao, K. (2026). Advances in RPGR gene therapy for X‑linked retinitis pigmentosa: From preclinical insights to clinical application (Review). International Journal of Molecular Medicine, 57, 52. https://doi.org/10.3892/ijmm.2025.5723
MLA
Long, Y., Qi, J., Zhang, W., Qin, H., Yao, K."Advances in RPGR gene therapy for X‑linked retinitis pigmentosa: From preclinical insights to clinical application (Review)". International Journal of Molecular Medicine 57.3 (2026): 52.
Chicago
Long, Y., Qi, J., Zhang, W., Qin, H., Yao, K."Advances in RPGR gene therapy for X‑linked retinitis pigmentosa: From preclinical insights to clinical application (Review)". International Journal of Molecular Medicine 57, no. 3 (2026): 52. https://doi.org/10.3892/ijmm.2025.5723
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