Retinoblastoma (RB) is the most common intraocular malignancy in children, accounting for approximately 11% of all cancers diagnosed in children under the age of one. Although its incidence is relatively low-about 1 in 15,000 to 20,000 live births-RB has a high risk of intracranial metastasis via the optic nerve, often leading to poor prognosis in advanced cases. Recent advances in administration routes, such as intravitreal and intra-arterial chemotherapy, have significantly improved eye preservation rates. However, these strategies are limited by cumulative retinal toxicity and drug resistance. In refractory cases, enucleation remains the only definitive treatment to prevent extraocular spread and death. In light of these challenges, current research efforts are focused on developing novel targeted therapies that enhance anti-tumor efficacy while minimizing local toxicity. In this context, we introduce a first-in-class siRNA-based drug targeting NUDT21, which promotes tumor regression by modulating the 3'UTR tail of SMC1A, thereby suppressing tumor cell proliferation. Importantly, the siRNA drug selectively targets tumor cells, offering a favorable safety profile compared to conventional chemotherapeutic regimens. Given that both the target (NUDT21) and the mode of administration (intraocular siRNA injection) are novel in retinoblastoma treatment, there is an urgent need for early-phase investigator-initiated clinical research. This study is therefore designed to assess the short-term safety and preliminary efficacy of NUDT21 siRNA in patients with refractory retinoblastoma, and to provide an evidence base for future large-scale clinical trials.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
2
It is performed for intravitreal chemotherapy.
Fudan Eye & ENT Hospital
Shanghai, China
RECRUITINGIncidence of Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) are defined as any unfavorable or unintended sign, symptom, or disease temporally associated with the administration of intravitreal siRNA therapy, whether or not considered related to the drug. Use CTCAE v5.0 (Common Terminology Criteria for Adverse Events) for grading severity.
Time frame: 6 months
Tumor size
Tumor size will be assessed by measuring tumor thickness (height) from the retinal surface to the apex of the lesion on optical coherence tomography (OCT) scan. Serial OCT scans will be used to track tumor regression or progression over time. This outcome aims to assess anatomical response to treatment and provide imaging-based evidence of therapeutic efficacy.
Time frame: 6 months
Retinal function
Photopic flicker electroretinography (ERG) will be conducted in accordance with ISCEV standards, typically using a 30 Hz stimulus. The amplitude will be measured and compared pre- and post-treatment. This outcome will assess the potential impact of the investigational therapy on cone system integrity and retinal functional preservation.
Time frame: 6 months
Target engagement
We will measure the concentrations of NUDT21 and SMC1A proteins in aqueous humor samples using enzyme-linked immunosorbent assay (ELISA) before and after treatment. This assessment will confirm pharmacodynamic target engagement of the NUDT21 siRNA therapy by evaluating changes in NUDT21 and downstream effector SMC1A expression levels.
Time frame: 6 months
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