Gene Therapy for Phenylketonuria
Recruiting in Palo Alto (17 mi)
+2 other locations
Age: 18 - 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: NGGT INC.
Must not be taking: Kuvan, Palynziq
Disqualifiers: Non-PAH PKU, Liver disease, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This is a Phase 1/2, open-label, multiple-center, dose escalation and cohort expansion study to evaluate the safety and efficacy of NGGT002 in adult subjects with classic Phenylketonuria (PKU). NGGT002 is an rAAV8 based vector carrying a functional copy of the human PAH gene.
Participants will receive a single administration of NGGT002 and will be followed for safety and efficacy for 5 years.
Will I have to stop taking my current medications?
Yes, participants must stop taking their current PKU medications like Kuvan or Palynziq at least 28 days before joining the trial.
What data supports the effectiveness of the treatment NGGT002 for Phenylketonuria?
Research shows that using a similar gene therapy approach with adeno-associated virus (AAV) vectors in mice has successfully reduced high levels of phenylalanine, a harmful substance in PKU, to near-normal levels. This suggests that NGGT002, which likely uses a similar method, could be effective in treating PKU.
12345Is the gene therapy for phenylketonuria safe for humans?
Research on a similar gene therapy using an adeno-associated virus (AAV) vector in mice showed no adverse effects at high doses, with only minor and temporary changes in liver enzymes. This suggests the therapy could be safe, but more studies in humans are needed to confirm this.
16789How is the treatment NGGT002 for phenylketonuria different from other treatments?
NGGT002 is a gene therapy that uses a viral vector to deliver a healthy copy of the gene responsible for producing the enzyme phenylalanine hydroxylase (PAH), which is deficient in people with phenylketonuria. Unlike the standard treatment that requires lifelong dietary restrictions, this approach aims to provide a long-term solution by correcting the underlying genetic defect.
510111213Eligibility Criteria
Adults aged 18-55 with classic Phenylketonuria (PKU), severe PAH deficiency, and specific genetic mutations. Participants must have had high phenylalanine levels despite a restricted diet and not be well-controlled on existing PKU medications like Kuvan or Palynziq. They should agree to follow dietary guidelines and use effective contraception.Inclusion Criteria
I am willing and able to sign the consent form for this study.
I have classic PKU with confirmed PAH mutations and no enzyme activity.
I am between 18 and 55 years old.
+7 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive a single administration of NGGT002 gene therapy
1 day
1 visit (in-person)
Follow-up
Participants are monitored for safety and efficacy after treatment
5 years
Regular visits throughout the 5-year period
Participant Groups
The trial is testing NGGT002, a gene therapy using an rAAV8 vector to deliver a functional human PAH gene to adults with classic PKU. It's designed to see if this one-time treatment can safely improve the body's ability to process phenylalanine over five years.
1Treatment groups
Experimental Treatment
Group I: NGGT002Experimental Treatment1 Intervention
Low dose and high dose group:
Six to twelve patients will be enrolled into two cohorts at two dose levels. The safety of this study can be ensured by selecting the highest dose under the No Observed Adverse Effect Level (NOAEL) doses observed in preclinical toxicology studies.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University or Texas, Southwestern medical CenterDallas, TX
Rare Disease Research, LLCAtlanta, GA
Atlantic Health SystemMorristown, NJ
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Who Is Running the Clinical Trial?
NGGT INC.Lead Sponsor
NGGT (Suzhou) Biotechnology Co., Ltd.Lead Sponsor
References
Use of an adeno-associated virus serotype Anc80 to provide durable cure of phenylketonuria in a mouse model. [2022]Phenylketonuria (PKU) is the most common inborn error of metabolism of the liver, and results from mutations of both alleles of the phenylalanine hydroxylase gene (PAH). As such, it is a suitable target for gene therapy via gene delivery with a recombinant adeno-associated virus (AAV) vector. Here we use the synthetic AAV vector Anc80 via systemic administration to deliver a functional copy of a codon-optimized human PAH gene, with or without an intron spacer, to the Pahenu2 mouse model of PKU. Dose-dependent transduction of the liver and expression of PAH mRNA were present with both vectors, resulting in significant and durable reduction of circulating phenylalanine, reaching near control levels in males. Coat color of treated Pahenu2 mice reflected an increase in pigmentation from brown to the black color of control animals, further indicating functional restoration of phenylalanine metabolism and its byproduct melanin. There were no adverse effects associated with administration of AAV up to 5 × 1012 VG/kg, the highest dose tested. Only minor and/or transient variations in some liver enzymes were observed in some of the AAV-dosed animals which were not associated with pathology findings in the liver. Finally, there was no impact on cell turnover or apoptosis as evaluated by Ki-67 and TUNEL staining, further supporting the safety of this approach. This study demonstrates the therapeutic potential of AAV Anc80 to safely and durably cure PKU in a mouse model, supporting development for clinical consideration.
Long-Term Metabolic Correction of Phenylketonuria by AAV-Delivered Phenylalanine Amino Lyase. [2022]Phenylketonuria (PKU) is an inherited metabolic disorder caused by mutation within phenylalanine hydroxylase (PAH) gene. Loss-of-function of PAH leads to accumulation of phenylalanine in the blood/body of an untreated patient, which damages the developing brain, causing severe mental retardation. Current gene therapy strategies based on adeno-associated vector (AAV) delivery of PAH gene were effective in male animals but had little long-term effects on blood hyperphenylalaninemia in females. Here, we designed a gene therapy strategy using AAV to deliver a human codon-optimized phenylalanine amino lyase in a liver-specific manner. It was shown that PAL was active in lysing phenylalanine when it was expressed in mammalian cells. We produced a recombinant adeno-associated vector serotype 8 (AAV8) viral vector expressing the humanized PAL under the control of human antitrypsin (hAAT) promoter (AAV8-PAL). A single intravenous administration of AAV8-PAL caused long-term correction of hyperphenylalaninemia in both male and female PKU mice (strain Pahenu2). Besides, no obvious liver injury was observed throughout the treatment process. Thus, our results established that AAV-mediated liver delivery of PAL gene is a promising strategy in the treatment of PKU.
Phenylketonuria: a 21st century perspective. [2021]Phenylketonuria is the most prevalent inherited defect in amino acid metabolism. Owing to mutations in the gene encoding the enzyme phenylalanine hydroxylase, the essential amino acid phenylalanine cannot be hydroxylated to tyrosine and blood and tissue concentrations of phenylalanine increase. Untreated, phenylketonuria causes severe mental retardation, epilepsy and behavioral problems. The combined effect of neonatal screening and treatment has, however, meant that phenylketonuria is now a biochemical rather than a clinical diagnosis. Treatment consists of stringent dietary restriction of natural protein intake and supplementation of amino acids other than phenylalanine by a chemically manufactured protein substitute. Although clinical outcome on a phenylalanine-restricted diet is good, neuropsychological deficits are now known to exist in dietary-treated patients with phenylketonuria, and quality of life, nutritional condition and psychosocial outcome could probably also be improved. The need for new therapeutic approaches is being met by supplementation with tetrahydrobiopterin or large neutral amino acids, whilst development of the use of phenylalanine ammonia lyase, and, in the longer term, gene therapy and chaperone treatment holds promise. This Review provides an overview of the history of phenylketonuria, the challenges of treatment today and the treatment possibilities in the near future.
Gene therapy for phenylketonuria: phenotypic correction in a genetically deficient mouse model by adenovirus-mediated hepatic gene transfer. [2012]Classical phenylketonuria (PKU), which predisposes affected individuals to severe mental retardation, is caused by a deficiency of hepatic phenylalanine hydroxylase (PAH). A recombinant adenoviral vector containing the human PAH cDNA was constructed and administered to PAH-deficient mice (strain PAHenu2). The hyperphenylalaninemic phenotype of these animals was completely normalized within 1 week of treatment. Although this therapeutic effect did not persist, analysis of the relationship between hepatic PAH activity and serum phenylalanine levels indicated that only 10-20% of normal enzymatic activity in the mouse liver is sufficient to restore normal serum phenylalanine levels. These results demonstrate that PKU and other metabolic disorders secondary to hepatic deficiencies can be completely corrected by gene therapy when more persistent vector systems are developed.
Administration-route and gender-independent long-term therapeutic correction of phenylketonuria (PKU) in a mouse model by recombinant adeno-associated virus 8 pseudotyped vector-mediated gene transfer. [2013]Phenylketonuria (PKU) is an inborn error of metabolism caused by deficiency of the hepatic enzyme phenylalanine hydroxylase (PAH) which leads to high blood phenylalanine (Phe) levels and consequent damage of the developing brain with severe mental retardation if left untreated in early infancy. The current dietary Phe restriction treatment has certain clinical limitations. To explore a long-term nondietary restriction treatment, a somatic gene transfer approach in a PKU mouse model (C57Bl/6-Pahenu2) was employed to examine its preclinical feasibility. A recombinant adeno-associated virus (rAAV) vector containing the murine Pah-cDNA was generated, pseudotyped with capsids from AAV serotype 8, and delivered into the liver of PKU mice via single intraportal or tail vein injections. The blood Phe concentrations decreased to normal levels (
Phenylalanine ammonia lyase, enzyme substitution therapy for phenylketonuria, where are we now? [2013]Phenylketonuria (PKU) is an autosomal recessive genetic disorder in which mutations in the phenylalanine-4-hydroxylase (PAH) gene result in an inactive enzyme (PAH, EC 1.14.16.1). The effect is an inability to metabolize phenylalanine (Phe), translating into elevated levels of Phe in the bloodstream (hyperphenylalaninemia). If therapy is not implemented at birth, mental retardation can occur. PKU patients respond to treatment with a low-phenylalanine diet, but compliance with the diet is difficult, therefore the development of alternative treatments is desirable. Enzyme substitution therapy with a recombinant phenylalanine ammonia lyase (PAL) is currently being explored. This enzyme converts Phe to the harmless metabolites, trans-cinnamic acid and trace ammonia. Taken orally and when non-absorbable and protected, PAL lowers plasma Phe in mutant hyperphenylalaninemic mouse models. Subcutaneous administration of PAL results in more substantial lowering of plasma and significant reduction in brain Phe levels, however the metabolic effect is not sustained following repeated injections due to an immune response. We have chemically modified PAL by pegylation to produce a protected form of PAL that possesses better specific activity, prolonged half-life, and reduced immunogenicity in vivo. Subcutaneous administration of pegylated molecules to PKU mice has the desired metabolic response (prolonged reduction in blood Phe levels) with greatly attenuated immunogenicity.
Evaluation of orally administered PEGylated phenylalanine ammonia lyase in mice for the treatment of Phenylketonuria. [2022]Phenylketonuria (PKU), a Mendelian autosomal recessive phenotype (OMIM 261600), is an inborn error of metabolism causing impaired postnatal cognitive development in the absence of treatment. We used the Pah(enu2/enu2) PKU mouse model to study oral enzyme substitution therapy with various chemically modified formulations of phenylalanine ammonia lyase (Av-p.C503S/p.C565S/p.F18A PAL). In vivo studies with the most therapeutically effective formulation (5kDa PEG-Av-p.C503S/p.C565S/p.F18A PAL) revealed that this conjugate, given orally, yielded statistically significant (p=0.0029) and therapeutically relevant reduction (~40%) in plasma phenylalanine (Phe) levels. Phe reduction occurred in a dose- and loading-dependent manner; sustained clinically and statistically significant reduction of plasma Phe levels was observed with treatment ranging between 0.3 IU and 9 IU and with more frequent and smaller dosings. Oral PAL therapy could potentially serve as an adjunct therapy, perhaps with dietary treatment, and will work independently of phenylalanine hydroxylase (PAH), correcting such forms of hyperphenylalaninemias regardless of the PAH mutations carried by the patient.
Safety profile of recombinant adeno-associated viral vectors: focus on alipogene tiparvovec (Glybera®). [2014]There has been great interest over the past two decades in developing gene therapies (GTs) to treat a variety of diseases; however, translating research findings into clinical treatments have proved to be a challenge. A major milestone in the development of GT has been achieved with the approval of alipogene tiparvovec (Glybera(®)) in Europe for the treatment of familial lipoprotein lipase deficiency. At this important stage with the evolution of GT into the clinic, this review will examine the safety aspects GT with adeno-associated virus (AAV) vectors. The topics that will be covered include acute reactions, immunological reactions to the AAV capsid and expressed transgene, viral biodistribution and shedding, DNA integration and carcinogenicity. These safety aspects of GT will be discussed with a focus on alipogene tiparvovec, in addition to other AAV vector GT products currently in clinical development.
Phenylalanine ammonia-lyase modified with polyethylene glycol: potential therapeutic agent for phenylketonuria. [2018]Phenylketonuria (PKU) is an autosomal recessive genetic disease caused by the defects in the phenylalanine hydroxylase (PAH) gene. Individuals homozygous for defective PAH alleles show elevated levels of systemic phenylalanine and should be under strict dietary control to reduce the risk of neuronal damage associated with high levels of plasma phenylalanine. Researchers predict that plant phenylalanine ammonia-lyase (PAL), which converts phenylalanine to nontoxic t-cinnamic acid, will be an effective therapeutic enzyme for the treatment of PKU. The problems of this potential enzyme therapy have been the low stability in the circulation and the antigenicity of the plant enzyme. Recombinant PAL originated from parsley (Petroselinum crispum) chemically conjugated with activated PEG2 [2,4-bis(O-methoxypolyethyleneglycol)-6-chloro-s-triazine] showed greatly enhanced stability in the circulation and was effective in reducing the plasma concentration of phenylalanine in the circulation of mice. PEG-PAL conjugate will be an effective therapeutic enzyme for the treatment of PKU.
Progress toward cell-directed therapy for phenylketonuria. [2021]Phenylketonuria (PKU) is one of the most common inborn errors of metabolism with an annual incidence of approximately 1:16,000 live births in North America. Contemporary therapy relies upon lifelong dietary protein restriction and supplementation with phenylalanine-free medical foods. This therapy is expensive and unpalatable; dietary compliance is difficult to maintain throughout life. Non-adherence to the diet is associated with learning disabilities, adult-onset neurodegenerative disease, and maternal PKU syndrome. The fervent dream of many individuals with PKU is a more permanent cure for this disease. This paper will review ongoing efforts to develop viable cell-directed therapies, in particular cell transplantation and gene therapy, for the treatment of PKU.
Long-term correction of murine phenylketonuria by viral gene transfer: liver versus muscle. [2021]Current therapy for phenylketonuria (PKU) consists of life-long dietary restriction of phenylalanine (Phe), which presents problems of adherence for patients. Alternative therapies under investigation include, among others, the use of gene therapy to provide copies of wild-type, non-mutant, phenylalanine hydroxylase (PAH) enzyme. Expression of PAH in both liver (the usual metabolic source of this enzyme) and skeletal muscle is under investigation. Liver gene therapy, using a viral vector based on the adeno-associated viruses (AAVs), provided effective clearance of serum Phe that was sustained for 1 year in some mice. In order for PAH expression to be effective in skeletal muscle, the essential metabolic cofactor, tetrahydrobiopterin (BH(4)), must also be provided, either by supplementation or gene therapy. Both these approaches were effective. When transgenic PKU mice that constitutively expressed PAH in muscle were given intraperitoneal supplementation with BH(4), this produced (transient) effective clearance of Phe to normal levels. In addition, use of an AAV vector containing the genes for PAH, and for two key synthetic enzymes for BH(4), provided substantial and long-lasting correction (more than 1 year) of blood Phe levels when injected into skeletal muscle of PKU mice. These two strategies provide promising treatment alternatives for the management of PKU in patients.
State-of-the-Art 2019 on Gene Therapy for Phenylketonuria. [2023]Phenylketonuria (PKU) is considered to be a paradigm for a monogenic metabolic disorder but was never thought to be a primary application for human gene therapy due to established alternative treatment. However, somewhat unanticipated improvement in neuropsychiatric outcome upon long-term treatment of adults with PKU with enzyme substitution therapy might slowly change this assumption. In parallel, PKU was for a long time considered to be an excellent test system for experimental gene therapy of a Mendelian autosomal recessive defect of the liver due to an outstanding mouse model and the easy to analyze and well-defined therapeutic end point, that is, blood l-phenylalanine concentration. Lifelong treatment by targeting the mouse liver (or skeletal muscle) was achieved using different approaches, including (1) recombinant adeno-associated viral (rAAV) or nonviral naked DNA vector-based gene addition, (2) genome editing using base editors delivered by rAAV vectors, and (3) by delivering rAAVs for promoter-less insertion of the PAH-cDNA into the Pah locus. In this article we summarize the gene therapeutic attempts of correcting a mouse model for PKU and discuss the future implications for human gene therapy.
Gene therapy for phenylketonuria. [2019]Classical phenylketonuria (PKU) is an autosomal recessive disorder caused by a deficiency of hepatic phenylalanine hydroxylase (PAH). Three different vector systems have been developed to examine the potential of somatic gene therapy for the treatment of PKU. Recombinant retroviral vectors and DNA/protein complexes can efficiently transduce PAH-deficient hepatocytes in vitro, but their present application is limited by their low transduction efficiency in vivo. In contrast, infusion of a recombinant adenoviral vector expressing the human PAH cDNA into the portal circulation of PAH-deficient mice restores 10-80% of normal hepatic PAH activity and completely normalizes serum phenylalanine levels. At present, this effect is transient and re-administration has no further effect. However, this result suggests that PKU can be completely corrected by somatic gene therapy as more persistent vectors are developed.