Propionic Acidemia
Conditions
Brief summary
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.
Interventions
DRUGAAVrh10-PCCA low dose
AAVrh10-PCCA (Dose of 2 x 10\^12 vg per kg body weight) is an adeno-associated viral vector containing the adeno-associated virus terminal repeat sequences flanking a transgene cassette harboring the cytomegalovirus (CMV) immediate-early enhancer and beta actin promoter, the human PCCA cDNA, and the bovine growth hormone polyadenylation sequence.
DRUGAAVrh10-PCCA middle dose
AAVrh10-PCCA (Dose of 8 x 10\^12 vg per kg body weight) is an adeno-associated viral vector containing the adeno-associated virus terminal repeat sequences flanking a transgene cassette harboring the cytomegalovirus (CMV) immediate-early enhancer and beta actin promoter, the human PCCA cDNA, and the bovine growth hormone polyadenylation sequence.
DRUGAAVrh10-PCCA high dose
AAVrh10-PCCA (Dose of 3.2 x 10\^13 vg per kg body weight) is an adeno-associated viral vector containing the adeno-associated virus terminal repeat sequences flanking a transgene cassette harboring the cytomegalovirus (CMV) immediate-early enhancer and beta actin promoter, the human PCCA cDNA, and the bovine growth hormone polyadenylation sequence.
Sponsors
Mayo Clinic
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Each group will receive AAVrh10-PCCA. The first cohort will receive the low dose, the second cohort the medium dose, and the third cohort the high dose.
Eligibility
Sex/Gender
ALL
Age
6 Months to 2 Years
Healthy volunteers
No
Inclusion criteria
* 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.
Exclusion criteria
* 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of treatment-emergent adverse events | 7 years | Total number of treatment-emergency adverse events. Adverse events include serious adverse events, lab safety tests, vital signs, and dose-limiting toxicities. |
Countries
United States
Contacts
CONTACTClinical Genomics Clinical Research Team
CONTACTWyatt Anians, M.S., CCRP
PRINCIPAL_INVESTIGATORDavid R. Deyle, MD
Mayo Clinic
Outcome results
None listed