What is Retinitis Pigmentosa?
 

Retinitis Pigmentosa (RP) is a genetically heterogeneous retinal degenerative disorder characterized pathologically by progressive photoreceptor cell death and retinal pigment epithelium (RPE) atrophy. Common clinical manifestations include night blindness, progressive visual field constriction, and gradual loss of central vision. Typical fundoscopic findings reveal bone spicule-like pigment deposits, generalized attenuation of retinal vessels, and waxy pallor of the optic disc, constituting the classic "triad." Research indicates that RP pathogenesis is closely associated with multiple gene mutations and protein metabolism abnormalities.

Based on inheritance patterns, RP is classified into three main types: autosomal dominant (adRP, accounting for approximately 15%–25%), autosomal recessive (arRP, approximately 5%–20%), and X-linked (XLRP, approximately 10%–15%). The global prevalence of RP is approximately 1/3,000–1/7,000, with an estimated prevalence of 1/4,000 in China, affecting over 1.5 million individuals.
 

Pathogenesis
 

Retinitis Pigmentosa exhibits high genetic heterogeneity, with over 90 causative genes identified to date (some common ones shown in the figure below), primarily involving point mutations. The core pathogenic mechanism involves gene mutations leading to abnormal synthesis or functional loss of photoreceptor-specific proteins (such as rhodopsin), triggering a cascade of pathological reactions.

Two major initial injuries result directly from pathogenic gene mutations: First, misfolded mutant proteins accumulate in the endoplasmic reticulum (e.g., RHO gene mutations), triggering the unfolded protein response; when endoplasmic reticulum stress persists and cannot be compensated, it activates the intrinsic apoptotic pathway through calcium ion release and effector molecules such as caspase-12. Second, mutations in cilia-related genes (e.g., RPGR) disrupt intraflagellar transport function, impairing outer segment disc renewal, disturbing cGMP metabolism and calcium ion homeostasis; the sustained high calcium environment activates calcium-dependent proteases, subsequently damaging the cytoskeleton and initiating apoptosis.

Concurrently, the high oxygen consumption of photoreceptor cells and the abundance of polyunsaturated fatty acids in their outer segments render them highly susceptible to oxidative stress under genetic predisposition. Excessive accumulation of reactive oxygen species leads to widespread lipid peroxidation, protein damage, and DNA strand breaks, directly exacerbating cellular damage and activating apoptotic signaling. Autophagy function becomes dysregulated in this process: initially enhanced as an adaptive response, but often followed by autophagic flux blockade, with accumulation of undegraded toxic substrates that paradoxically become factors exacerbating cellular stress.
 

Image Retinitis Pigmentosa: Progress in Molecular Pathology and Biotherapeutical Strategies

Cell damage and death directly release damage-associated molecular patterns (DAMPs), which can activate various pattern recognition receptors. This triggers cell death cascades through two main pathways: On one hand, DAMPs can induce cells to produce inflammatory cytokines such as TNF-α, which activate death receptors (e.g., TNFR1), initiating the extrinsic apoptotic pathway, or when caspase-8 is inhibited, shift to the RIPK1/RIPK3/MLKL-mediated necroptosis pathway. On the other hand, DAMPs (such as ATP, crystals) can directly activate inflammasomes like NLRP3, leading to caspase-1 activation, cleavage of gasdermin D (GSDMD), and induction of pyroptosis, while simultaneously releasing pro-inflammatory cytokines like IL-1β and IL-18, amplifying the inflammatory response. Additionally, during the above processes (particularly oxidative stress), if accompanied by impaired GPX4 function, accumulation of lipid peroxidation products can induce ferroptosis. Ultimately, multiple cell death pathways—apoptosis, necroptosis, pyroptosis, and ferroptosis—intersect and synergize, collectively driving the progressive loss of rod and cone photoreceptors.

Image Retinitis Pigmentosa: Progress in Molecular Pathology and Biotherapeutical Strategies
 

Gene Therapy
 

Gene Replacement Therapy: Primarily applicable to autosomal recessive RP (arRP) and X-linked RP (XLRP). This approach utilizes recombinant adeno-associated virus (rAAV) vectors to deliver functional genes to retinal cells, compensating for proteins that are absent or dysfunctional due to gene mutations. Serotypes AAV2, AAV5, AAV8, and AAV9 are widely used, administered via intravitreal or subretinal injection. Luxturna® (voretigene neparvovec) has been approved for RPE65 gene mutation-associated Leber congenital amaurosis. Multiple clinical trials (Phase 1/2 to Phase 3) targeting XLRP caused by RPGR mutations (e.g., AAV5-RPGR) and PDE6B mutations (e.g., AAV2/5-hPDE6B) are underway, aiming to delay photoreceptor degeneration.

Gene Silencing Technologies: Primarily applicable to autosomal dominant RP (adRP), targeting dominant-negative mutations by suppressing mutant allele expression.

1.RNA Interference (RNAi) Technology: Designs small interfering RNAs (siRNAs) or microRNAs (miRNAs) to target and degrade mutant gene mRNA, reducing toxic protein accumulation (e.g., certain RHO gene mutations).

2.Antisense Oligonucleotide (ASO) Technology: Modulates pre-mRNA splicing or promotes degradation of mutant mRNA to restore function. ASO drugs (e.g., Patisiran) have been approved for other diseases, providing reference for RP treatment.
 

Mouse Models
 

P23H-RHO Mice: Model the most common human RHO mutation (Pro23His), exhibiting progressive rod cell death followed by cone cell involvement; widely used for pathogenesis studies, drug screening, and gene therapy validation.

S334ter-RHO Mice: Truncating mutation in the RHO gene causes C-terminal deletion of rhodopsin protein, with more rapid disease progression—outer segment abnormalities appear within 1 week after birth, and rod cells are almost completely lost by 3 weeks.

RHO Knockout Mice: Completely lack rhodopsin expression, with abnormal rod cell development and failure of outer segment formation, but relatively slow apoptosis; used to study rhodopsin's role in photoreceptor development and function.

RPGR Knockout Mice: Completely lack RPGR protein; early photoreceptor development appears normal after birth, but outer segment renewal is impaired, with rod cell death beginning around 4-6 months, followed by cone cell involvement; a classic model for studying RPGR loss-of-function pathology.

RPGRrd9 Mice: Carry a deletion mutation in exon 9 of the RPGR gene, exhibiting progressive rod cell degeneration and reduced ERG amplitudes; commonly used to evaluate therapeutic intervention time windows.
 

MingCeler Biotech Supports Gene Therapy
 

Gene therapy offers hope for rare diseases, but its development and validation critically depend on animal model support. MingCeler Biotech has developed multiple rare disease mouse models using its proprietary TurboMice™ technology. The TurboMice™ platform overcomes technical challenges associated with long mouse model generation cycles and low success rates for complex models, enabling editing at virtually any target gene locus and producing complete homozygous gene-edited mouse models directly from embryonic stem cells in as little as 2 months.

MingCeler Biotech can customize various RP mouse models according to client needs, including P23H-RHO mice, S334ter-RHO mice, RHO knockout mice, RPGR knockout mice, RPGRrd9 mice, and others. We welcome inquiries from researchers!

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