Phase 1 Study of Intravenous Administration of a Serotype rh.10 Replication Deficient Adeno-associated Virus Gene Transfer Vector Expressing the Human Propionyl-CoA Carboxylase cDNA (AAVrh10-PCCA) to Individuals With Propionic Acidemia
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- Mayo Clinic
- 入组人数
- 9
- 试验地点
- 1
研究概览
简要总结
Propionic acidemia is a genetic metabolic disorder characterized by metabolic acidosis, ketosis, vomiting, lethargy, cognitive impairment, and risk of death. It results from loss of function of the mitochondrial enzyme propionyl-CoA carboxylase and can be due to disease-causing variants in the PCCA gene, leading to accumulation of propionyl-CoA and its toxic metabolites. The purpose of this trial is to evaluate the safety and potential therapeutic benefit of an AAV-based gene therapy for propionic acidemia in patients with genetically confirmed biallelic variants in PCCA.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 6 Months 至 2 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age six months to 2 years of age at day of vector infusion. For those <1 year of age they must have been ≥37 weeks gestational age at the time of birth and without other conditions/comorbidities that in the opinion of the Investigator may interfere with the interpretation of study results.
- •Confirmed diagnosis of propionic acidemia with biallelic PCCA gene mutations based on molecular genetic testing.
- •Study participants must have a diagnosis of neonatal-onset propionic acidemia with a documented episode of decompensation that can include any of the following findings: lethargy, poor feeding, irritability, vomiting, encephalopathy, respiratory failure, seizures, coma, metabolic acidosis, lactic acidosis, ketonuria, hypoglycemia, hyperammonemia, and cytopenias or history of recurrent hospitalizations.
- •Parents or legal guardians of study participants must agree to comply in good faith with the conditions of the study, including attending all of the required baseline and follow-up assessments, and parents or legal guardians must give consent for their child's participation.
排除标准
- •Hemoglobin <10 g/dl
- •Platelet count < 100,000 per mm3
- •Liver Enzyme ALT/AST >2.5 ULN
- •Direct Bilirubin > 1.5
- •Active viral infection (includes HIV or serology positive for hepatitis B or C).
- •Previous liver transplant
- •Subjects with active decompensation as demonstrated by a pH < 7.3, bicarbonate < 15 mmol/L, NH3 > 75 mcmol/L, lactate > 2.5 mmol/L, urine ketones
- •Previously received gene therapy or messenger ribonucleic acid (mRNA) treatments for PA.
- •Grade 3 or 4 heart failure according to the Modified Ross Heart Failure Classification for Children or the New York Heart Association Classification.
- •Family does not want to disclose patient's study participation with primary care physician and other medical providers.
研究组 & 干预措施
Gene Therapy Third Cohort (3 patients)
AAVrh10-PCCA, single dose of 3.2 x 10^13 vg per kilogram of body weight (last three patients), IV administration
干预措施: AAVrh10-PCCA high dose (Drug)
Gene Therapy First Cohort (3 patients)
AAVrh10-PCCA, single dose of 2 x 10^12 vg per kilogram of body weight (first three patients), IV administration
干预措施: AAVrh10-PCCA low dose (Drug)
Gene Therapy Second Cohort (3 patients)
AAVrh10-PCCA, single dose of 8 x 10^12 vg per kilogram of body weight (middle three patients), IV administration
干预措施: AAVrh10-PCCA middle dose (Drug)
研究者
David R. Deyle
Principal Investigator
Mayo Clinic