Targeting NUDT21 siRNA Drugs for Patients With Refractory Retinoblastoma

Targeting NUDT21 siRNA Drugs for Patients With Refractory Retinoblastoma (A Prospective Pilot Study)

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 Overview

• Status: Recruiting
• Conditions: Retinoblastoma; Refractory
• Intervention / Treatment: Drug: Targeting NUDT21 siRNA drugs

• Study Type: Interventional
• Enrollment (Estimated): 2
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Chen Zhao, MD; Phone Number: 86-021-64377134; Email: dr_zhaochen@fudan.edu.cn
• Study Contact Backup: Name: Ruiqi Ma, MD; Email: ruiqi_ma@fudan.edu.cn

Study Locations

• China
  • Shanghai, China
    • Recruiting
    • Fudan Eye & ENT Hospital
    • Contact: Ruiqi Ma; Phone Number: +86 (021) 64377134; Email: ruiqi_ma@fudan.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients with retinoblastoma with a somatic mutation of the gene RB1 and active tumor in a single eye, or germinal mutation of RB1 with active tumor/s in an eye and the contralateral eye unaffected, enucleated or without tumor activity. In both cases, relapsed or refractory with the use of systemic, intraarterial or intravitreal chemotherapy or radiotherapy, in accordance with the availability at his/her referral site, in whom enucleation is the only recommended treatment under opinion of the medical team treating the case at the originating referral site. But the patient has a strong desire to preserve the eye.
2. Normal renal function: serum creatinine: < 45 μmol/L (0-2 years); < 57 μmol/L (3-6 years); < 60 μmol/L (7-10 years); < 80 μmol/L (11-13 years).
3. Normal Hepatic function: serum ALT: < 0,52 μkat/L (de 9 months -12 years); serum AST: 61-80 g/L (8 months - 5 years); 63-83 g/L (5-9 years); 63-82 g/L (9-12 years).
4. Age greater than 6 months at the time of inclusion in the study.
5. Sign the informed consent form and be willing to follow up at the specified time.

Exclusion Criteria:

1. Presence of factors that require immediate enucleation of the affected eye such as glaucoma, rubeosis iridis, anterior chamber involvement.
2. Comorbidities: Uncontrolled epilepsy with anticonvulsant treatment, cardiac disease not compensated by treatment.
3. Active Infections.
4. Other chronic or active acute diseases that under the criterion of the researcher were an exclusion criterion.
5. History of having received attenuated or live vaccines in the 30 days prior to inclusion in the study.
6. Any cause of Immunosuppression.
7. Trilateral Retinoblastoma.
8. Extraocular spread.
9. History of having received treatment for retinoblastoma with chemotherapy or radiation therapy by any means within 30 days prior to inclusion in the study.
10. Patients who can not complete the study procedures.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Intravitreal chemotherapy in patients with refractory retinoblastoma; Prior to the first administration of the targeted drug, enrolled patients underwent peripheral blood sampling and comprehensive clinical evaluation. Intravitreal injections of the targeted drug were administered at a dosage of 100-200 μg (100 μg for patients under 2 years of age; 200 μg for patients aged 2 years and above) on Day 1 of Weeks 1, 3, and 7. Aqueous humor samples were collected at the time of injection during Weeks 1, 3, and 7. Clinical assessments were conducted monthly, with continuous follow-up extending through Week 24.

Drug: Targeting NUDT21 siRNA drugs; It is performed for intravitreal chemotherapy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence 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.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	6 months

Collaborators and Investigators

• Sponsor: Eye & ENT Hospital of Fudan University
• Collaborators: The Eye Hospital of Wenzhou Medical University
• Investigators: Principal Investigator: Chen Zhao, MD, Fudan Eye & ENT Hospital; Study Director: Kang Xue, MD, Fudan Eye & ENT Hospital; Study Director: Kang Zhang, MD, The Eye Hospital of Wenzhou Medical University; Study Director: Jiang Qian, MD, Fudan Eye & ENT Hospital

Study record dates

Study Major Dates

• Study Start (Actual): December 20, 2024
• Primary Completion (Estimated): September 30, 2025
• Study Completion (Estimated): September 30, 2025

Study Registration Dates

• First Submitted: May 16, 2024
• First Submitted That Met QC Criteria: May 16, 2024
• First Posted (Actual): May 22, 2024

Study Record Updates

• Last Update Posted (Actual): June 26, 2025
• Last Update Submitted That Met QC Criteria: June 20, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: retinoblastoma; intravitreal Chemotherapy
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Eye Diseases; Neoplasms, Glandular and Epithelial; Eye Diseases, Hereditary; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Eye Neoplasms; Retinal Diseases; Retinal Neoplasms; Retinoblastoma
• Other Study ID Numbers: FDEENT-20241031

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: IPD will be shared upon requirement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No