An Open-Label, Non-Randomized Study to Evaluate the Efficacy and Safety of ASO-GNAO1 (Tianasen) in Patients With GNAO1-Encephalopathy With Epilepsy and Movement Disorders Following Repeated Intrathecal Dose Escalation.
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 5
- 试验地点
- 1
- 主要终点
- Change in monthly seizure frequency
研究概览
简要总结
The goal of this clinical trial is to evaluate the efficacy and safety of the investigational drug ASO-GNAO1 (Tianasen) in pediatric patients with c.607G>A mutation in the GNAO1 gene associated with epilepsy and neurodevelopmental disorder. The main questions it aims to answer are:
- Does intrathecal administration of ASO-GNAO1 slow or halt the progression of motor and cognitive symptoms?
- Is ASO-GNAO1 safe and well-tolerated in this patient population?
- What is the appropriate therapeutic dose?
This is an open-label study without a placebo control group due to the rare and severe nature of the disease. All participants will receive the active drug.
Participants will:
Receive escalating doses of ASO-GNAO1 via intrathecal injection over a 12-month period.
Undergo frequent neurological assessments, biomarker testing, and safety monitoring.
详细描述
The variant c.607G>A in the GNAO1 gene is a gain-of-function (GOF) mutation associated with epilepsy and neurodevelopmental disorder.
ASO-GNAO1 (Tianasen) is an investigational antisense oligonucleotide (ASO) therapy designed for the treatment of GNAO1-encephalopathy. Its mechanism of action is allele-specific suppression of the mutant GNAO1 protein expression at the mRNA level. The compound mediates the degradation of mutant mRNA or inhibits its translation, thereby halting the synthesis of the pathogenic protein implicated in disease progression. This targeted suppression is anticipated to mitigate neurodegenerative processes and facilitate partial or complete restoration of neuronal function.
The drug candidate was identified through a screening platform analogous to that used for the development of Milasen, an FDA-authorized personalized ASO therapy for Batten disease. In vitro studies have demonstrated that ASO-GNAO1 (Tianasen) achieves approximately 85% suppression of the mutant GNAO1 allele activity (c.607G>A mutation) while showing no significant effect on the wild-type allele, confirming its allele-specificity.
Background and Rationale. GNAO1 encephalopathy is a severe, debilitating monogenic neurodevelopmental disorder of childhood onset, characterized by progressive motor dysfunction and drug-resistant epilepsy and hyperkinesis. Currently, there are no approved disease-modifying therapies, and management is limited to palliative and symptomatic care. The disease course is progressive, leading to severe developmental delay, profound disability, and premature mortality.
The rationale for this first-in-human study is to evaluate the potential of ASO-GNAO1 (Tianasen) to alter the natural history of the disease in a population with no alternative effective treatment options.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 1 Year 至 14 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Informed Consent: Written informed consent from the parent(s) or legal guardian(s) of the patient and the child's assent (where applicable based on age and cognitive ability), obtained prior to the initiation of any study-related procedures.
- •Age: Male or female children aged 1 year and older (≥1 year) until 14 years at the time of informed consent signing.
- •Diagnosis: A confirmed a c.607G>A variant in of GNAO1 gene based on genetic testing, and a clinical presentation that includes both epilepsy and movement disorders.
- •Treatment Resistance:
- •For seizures: Documented resistance to antiseizure medications prior to screening, defined as the persistence of seizures despite adequate trials of at least two appropriately dosed antiseizure medications.
- •For non-epileptic hyperkinesias/dystonia: Documented resistance to anti-hyperkinetic medications prior to screening, defined as the persistence of debilitating hyperkinesias or dystonic attacks despite adequate trials of at least two appropriately dosed anti-hyperkinetic medications.
- •Contraception (for females of reproductive potential): For post- menarche female adolescents, a negative serum or urine pregnancy test at screening and agreement to use highly effective methods of contraception (e.g., hormonal implants, combined oral contraceptives, intrauterine device) throughout the study participation period.
排除标准
- •Unacceptable Risk: Any concurrent severe medical, neurological, or psychiatric condition, or any other significant circumstance (e.g., unstable clinical status) that, in the judgment of the Investigator, could significantly increase the risk associated with study participation or the administration of the investigational product, or could interfere with the interpretation of study results.
- •Impossibility of Intervention: Any anatomical abnormality, coagulation disorder, active infection, or other condition that constitutes a contraindication to or precludes the safe performance of repeated lumbar punctures for intrathecal administration of the study drug.
- •Pregnancy or Lactation: Pregnancy, lactation, or intention to become pregnant during the study period.
- •Concurrent Experimental Therapy: Receipt of any other investigational drug, device, or biological product within 1 month prior to screening or within a period of at least 5 half-lives of that product (whichever is longer).
- •Protocol Compliance: Any other disease, condition, or behavioral factor that, in the opinion of the Investigator, could compromise the patient's safety, preclude adherence to the protocol schedule, or interfere with the study conduct and endpoint assessments. Age: 14 years and older
研究组 & 干预措施
GNAO1 c.607G>A carriers
Patients enrolled based on the screening results will receive intrathecal administration of the ASO drug Tianasen, starting with a minimum initial dose of 0.3 mg/kg. The drug dose will be escalated every 2 weeks until the expected therapeutic dose of 1.2 mg/kg is reached. With good tolerability, the dose may be further increased to 1.5 mg/kg.
Upon reaching the final dose level, an interim analysis of the results from the dose escalation period (including PK, efficacy, and safety assessments) will be conducted. Based on the results of this analysis, a decision will be made regarding the continuation of the study using the achieved dose.
The study may be terminated prematurely if the risk-benefit ratio is deemed unfavorable.
干预措施: Antisense oligonucleotide treatment (ASO) (Biological)
结局指标
主要结局
Change in monthly seizure frequency
时间窗: Baseline to Week 50
Change from Baseline in the number of seizure episodes per month. Unit of Measure: seizures per month
Change in total monthly duration of seizures
时间窗: Baseline to Week 50
Change from Baseline in the total duration of seizure episodes per month. Unit of Measure: minutes per month
Change in frequency of non-epileptic hyperkinetic and dystonic episodes
时间窗: Baseline to Week 50
Change in frequency of non-epileptic hyperkinetic and dystonic episodes Unit: episodes per month
Change in duration of non-epileptic hyperkinetic and dystonic episodes
时间窗: Baseline to Week 50
Change in duration of non-epileptic hyperkinetic and dystonic episodes Unit: minutes per month
次要结局
- Change in epileptiform activity index on EEG(Baseline, Week 46)
- Change in Barry-Albright Dystonia Scale score(Baseline, Week 46)
- Change in concomitant medication dosages(Baseline, Week 46)
- Change in Gross Motor Function Measure-88 total score(Baseline, Week 46)
- Change in Denver Developmental Screening Test developmental age(baseline and week 46)
- Change in Leiter-3 nonverbal IQ score(Baseline and week 46)