Gene Therapy for Ornithine Transcarbamylase Deficiency
Recruiting in Palo Alto (17 mi)
+25 other locations
Age: Any Age
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 3
Waitlist Available
Sponsor: Ultragenyx Pharmaceutical Inc
No Placebo Group
Pivotal Trial (Near Approval)
Prior Safety Data
Trial Summary
What is the purpose of this trial?This trial is testing DTX301, a treatment designed to help people with late-onset OTC deficiency, a condition that makes it hard for their bodies to process certain proteins. The treatment aims to improve the function of an enzyme that helps manage ammonia levels in the blood. Participants will be monitored for several years, with some continuing in a follow-up program for additional time.
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications, but if you are on daily ammonia scavenger therapy, you must be on a stable dose for at least 4 weeks before starting the trial.
What data supports the effectiveness of the treatment DTX301 for ornithine transcarbamylase deficiency?
Research using similar gene therapy approaches for ornithine transcarbamylase deficiency has shown that gene delivery can correct biochemical abnormalities and protect against high ammonia levels in animal models, suggesting potential effectiveness for DTX301.
12345How does the treatment DTX301 differ from other treatments for ornithine transcarbamylase deficiency?
DTX301 is a gene therapy that uses a viral vector to deliver a healthy copy of the OTC gene directly to the liver, aiming to correct the underlying genetic defect, unlike traditional treatments that may involve dietary management or liver transplantation.
14678Eligibility Criteria
This trial is for people with late-onset OTC deficiency who are on a stable dose of ammonia scavenger therapy and diet, have safe plasma ammonia levels, and agree to use effective contraception. It's not for those in other gene studies, with active hepatitis or significant liver issues, infections, conditions that risk participation or skew results, or detectable antibodies against the AAV8 capsid.Inclusion Criteria
From the time written informed consent through Week 128, females of childbearing potential and fertile males must consent to use highly effective contraception. If female, agree not to become pregnant. If male, agree not father a child or donate sperm
Your ammonia level in the blood on the first day before taking the medication is less than or equal to 200 µmol/L.
If you are on a diet that limits protein, your daily protein intake should not change by more than 20% for at least 4 weeks before screening.
+3 more
Exclusion Criteria
I am currently being treated for or have tested positive for hepatitis B or C.
I do not have any active infections.
I have severe liver inflammation or cirrhosis.
+4 more
Participant Groups
The study tests DTX301's ability to improve OTC function by maintaining safe ammonia levels without dietary protein restrictions or alternative meds. Participants will receive either DTX301 with oral corticosteroids or placebos for both and their efficacy will be compared.
2Treatment groups
Experimental Treatment
Group I: Placebo, Then DTX301Experimental Treatment5 Interventions
Participants receive single peripheral IV infusion of placebo. At week 64, participants receive single peripheral IV infusion of DTX301 in solution.
Group II: DTX301, Then PlaceboExperimental Treatment5 Interventions
Participants receive single peripheral intravenous (IV) infusion of DTX301 in solution. At week 64, participants receive single peripheral IV infusion of placebo.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of Arkansas for Medical SciencesLittle Rock, AR
University of CaliforniaLos Angeles, CA
The Hospital for Sick ChildrenToronto, Canada
University of ColoradoAurora, CO
More Trial Locations
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Who Is Running the Clinical Trial?
Ultragenyx Pharmaceutical IncLead Sponsor
References
In vivo assessment of mutations in OTC for dominant-negative effects following rAAV2/8-mediated gene delivery to the mouse liver. [2013]Mutant proteins have the potential to exert dominant-negative effects that might limit the therapeutic efficacy of their wild-type counterparts after gene transfer. For ornithine transcarbamylase (OTC) deficiency, in vitro studies have suggested the presence of dominant-negative effects, however, supporting in vivo studies have not been conducted. In this study, we exploited the capacity of recombinant adeno-associated virus (rAAV) 2/8 vectors to deliver transgenes to the mouse liver with high efficiency to determine whether expression of selected OTC mutant proteins exert inhibitory effects on endogenous wild-type OTC enzymatic activity. Using site-directed mutagenesis we constructed three OTC mutants with a theoretical or reported in vitro capacity to exert dominant-negative effects, and delivered these to the liver using rAAV2/8. Each mutation had been earlier identified in patients with OTC deficiency. Treated mice showed no increase in urinary orotic acid levels or reduction in OTC activity despite supra-physiological expression of the mutant proteins, consistent with an absence of dominant-negative effects. These data have important implications for the development of gene therapy strategies for OTC deficiency and validate a model system in which potential dominant-negative effects of specific mutations in prospective patients can be examined empirically before gene therapy.
Expression of wild-type and mutant human ornithine transcarbamylase genes in Chinese hamster ovary cells and lack of dominant negative effect of R141Q and R40H mutants. [2009]Chinese hamster ovary cultured cells were transformed to continuously express wild-type and two mutant ornithine transcarbamylase genes, R141Q and R40H. In addition, these cells were transfected to transiently express the same genes. The R141Q mutation abolishes the enzymatic activity, and the amount of "mature" protein present in transfected cells is equivalent to the wild type. The R40H mutation causes a reduction of enzymatic activity to approximately 26 to 35% of wild type concomitant with a significant reduction in the amount of protein present. Transfection with wild-type and mutant genes together in various proportions did not reveal dominant negative effects of the two mutations studied. This expression system can be used to examine the deleterious effect of private mutations or lack thereof in families with ornithine transcarbamylase deficiency as well as evaluate the potential dominant negative effects of gene delivery for treatment of ornithine transcarbamylase deficiency.
[Molecular characterization of a new mutation E122G of human ornithine transcarbamylase gene]. [2006]To determine the molecular basis of late onset ornithine transcarbamylase (OTC) deficiency in a Chinese family of Han nationality and the exon sequences of OTC gene of this patient.
A novel splice site mutation in OTC gene of a female with ornithine transcarbamylase deficiency and her asymptomatic mosaic father. [2022]Ornithine transcarbamylase deficiency is an X-linked disease with a wide range of clinical severity and manifestation age both in males and females. Here, we describe a case which is caused by a novel c.78-1G[A splice site mutation, which on mRNA level leads to a 1-bp deletion and a frameshift (c.78delG (p.C27Vfs*11)) in OTC exon 2 in a young girl. The same mutation has been detected in a mosaicstate in her asymptomatic father.
Developing adenoviral-mediated in vivo gene therapy for ornithine transcarbamylase deficiency. [2019]There are a number of reasons for choosing ornithine transcarbamylase (OTC) deficiency as a candidate for gene therapy: the gene has been cloned; the disorder is relatively common; the current clinical outcome is poor; and there are authentic animal models. In considering the development of gene therapy for OTC deficiency, we focused on the use of in vivo gene therapy with an adenoviral vector. Using the partially OTC-deficient sparse fur mouse we found transduction and expression could be achieved using an intravenous infusion of a recombinant adenovirus containing the OTC cDNA. The results were transient as a result of immune activation in response to the vector and vector-transduced cells. By modifying the adenoviral construct, creating an E1 deletion-E2 temperature-sensitive mutation, we blunted the cytotoxic T lymphocyte immune response and achieved correction of biochemical abnormalities for 2-3 months. We also found that transduction and expression following gene transfer occurred sufficiently rapidly to protect against acute hyperammonaemia within 24 h. Subsequent preclinical studies in mice and non-human primates demonstrated that E1-E4-deleted vectors had a substantially improved safety profile and similar efficacy. With this evidence of efficacy and safety of adenoviral vectors, we are embarking on a phase I trial of intravascular gene transfer using an E1-E4-deleted vector in adults with partial OTC deficiency.
Treatment of ornithine transcarbamylase deficiency in girls by auxiliary liver transplantation: conceptual changes in a living-donor program. [2019]Ornithine transcarbamylase (OTC) deficiency is an X-chromosome-linked genetic disorder resulting in hyperammonemia hepatic dysfunction, coma, and serious neurological sequelae. This report describes an experience in treating this condition with living-related liver transplantation.
Retroviral-mediated gene transfer of human ornithine transcarbamylase into primary hepatocytes of spf and spf-ash mice. [2012]The sparse fur (spf) and the sparse fur/abnormal skin and hair (spf-ash) mice are two murine models of the human X-linked disorder ornithine transcarbamylase (OTC) deficiency. A defective recombinant retrovirus, delta N2OTC was used to transduce primary hepatocytes derived from these mutant animals. Transduction of the primary cultures was highly efficient, with an average proviral copy number of 0.5-2 per cell in the population of transduced hepatocytes. Northern analysis and slot blots of total RNA isolated from transduced cells showed levels of human OTC mRNA to be equivalent to that present in normal human liver. Enzymatic assays demonstrated that a partial biochemical correction of the defect was achieved. After retroviral transduction, the hepatocytes were trypsinized and replated for long-term culture. Viability after replating exceeded 90%, indicating that the transduced cells might be useful for transplantation. The successful in vitro correction of OTC deficiency by this vector suggests that it will also be useful in somatic gene therapy experiments.
Ornithine transcarbamylase deficiency: a novel splice site mutation in a family with meiotic recombination and a new useful SNP for diagnosis. [2019]Ornithine transcarbamylase (OTC, EC 2.1.3.3) deficiency (OTCD; OMIM #311250) is known to be genetically very heterogeneous, with many cases occurring de novo, due to an exceptional instability of the OTC gene. We report a new G > T substitution in the first nucleotide of intron 2 and we describe also a novel SNP (IVS8 + 35 nt: G > T) with very convenient frequencies (62%/38%) for its use as an extra tool for OTCD diagnosis in cases of suspected deletions.