Gene Therapy for Phenylketonuria
Recruiting in Palo Alto (17 mi)
+15 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Sanofi
Disqualifiers: Liver disease, HIV, Hepatitis B, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This is a single group Phase 1/Phase 2, 1-arm, open-label study with SAR444836, an adeno-associated virus (AAV) vector-mediated gene transfer of human phenylalanine hydroxylase (PAH), for the treatment of adult participants with phenylketonuria (PKU) on a chronic, stable diet. The purpose of the study is to evaluate the safety and efficacy of SAR444836 in reducing phenylalanine (Phe) levels and in the elimination of a Phe restricted diet.
Participants will receive a one-time intravenous (IV) administration of SAR444836.
The study is constituted of 2 separate parts: a dose escalation part, and a dose expansion part where subsequent participants will be administered a safe and effective dose level identified during the dose escalation part. In both study parts, clinical and laboratory assessments will be collected to: a) assess the incidence of adverse events, and b) evaluate the effect of SAR444836 on reductions in blood Phe levels and maintenance of these Phe levels after elimination of a Phe restricted diet.
The study duration will be approximately 102 weeks (approximately 2 years) for each participant and includes a 6-week screening phase and 96-week follow-up period after SAR444836 administration.
There will be a total of 41 study visits. Many study visits may occur as remote visits and be performed by a qualified in-home service provider.
Actual study duration for an individual participant may be longer than 102 weeks due to the administration of SAR444836 to participants in Stage 1A in a serial fashion, or other factors such as delays in scheduling study visits.
Will I have to stop taking my current medications?
The trial information does not specify if you need to stop taking your current medications. However, you must maintain your current diet unless directed otherwise by the study protocol.
What data supports the effectiveness of the treatment SAR444836 for Phenylketonuria?
Research shows that using a virus to deliver a healthy version of the gene responsible for breaking down phenylalanine can significantly reduce its levels in the blood of mice with Phenylketonuria. This approach has been effective in both liver and muscle tissues, suggesting potential for long-term treatment in humans.
12345Is the gene therapy treatment SAR444836 safe for humans?
In studies using mice, the gene therapy using adeno-associated virus (AAV) vectors, like Anc80 and AAV8, showed no significant adverse effects, even at high doses. Minor changes in liver enzymes were observed but were not linked to any liver damage, indicating a promising safety profile for this approach.
13567How is the treatment SAR444836 for phenylketonuria different from other treatments?
SAR444836 is a gene therapy that uses a synthetic adeno-associated virus (AAV) vector to deliver a functional copy of the phenylalanine hydroxylase (PAH) gene directly to the liver, aiming to provide a long-term cure for phenylketonuria, unlike current treatments that mainly involve strict dietary restrictions.
12389Eligibility Criteria
Adults aged 18-65 with Phenylketonuria (PKU) due to PAH deficiency, who have been on a stable diet restricting phenylalanine. Participants must have had high plasma Phe levels in the past while on this diet and be willing to maintain their current diet for the trial's duration. They should not be able to bear children, have a BMI ≤ 35 kg/m2, and agree to use contraception.Inclusion Criteria
My blood tests show high phenylalanine levels twice, despite my diet.
My blood Phe levels were high twice in the last year despite my special diet.
Body mass index (BMI) ≤ 35 kg/m2
+10 more
Exclusion Criteria
Presence of neutralizing antibodies against the AAV SNY001 capsid
I do not have HIV, active hepatitis B or C, or any serious infection.
Abnormal liver function laboratory testing evidenced by alanine aminotransferase (ALT)>1.5X upper limit normal (ULN), aspartate transaminase (AST)>1.5X ULN, alkaline phosphatase >1.5X ULN, Total and direct bilirubin >1.5X ULN (bilirubin levels above the laboratory's normal range are acceptable in individuals with a documented history or laboratory evidence of Gilbert's Disease)
+1 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
6 weeks
Treatment
Participants receive a one-time intravenous administration of SAR444836
1 day
1 visit (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment, including clinical and laboratory assessments to evaluate the effect of SAR444836 on blood Phe levels
96 weeks
40 visits (remote and in-person)
Participant Groups
The study tests SAR444836, a gene therapy aiming to treat PKU by introducing a functional version of the PAH enzyme via an adeno-associated virus vector. It involves one IV administration followed by monitoring over approximately two years with up to 41 visits which may include remote assessments.
1Treatment groups
Experimental Treatment
Group I: SAR444836Experimental Treatment1 Intervention
Participants will receive a single dose of SAR444836 on Day 1
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University Hospitals Cleveland Medical Center- Site Number : 8400014Cleveland, OH
Medical University of South Carolina - Charleston - Jonathan Lucas Street- Site Number : 8400004Charleston, SC
Children's Hospital IMD Clinic- Site Number : 8400015Aurora, CO
UPMC Children's Hospital of Pittsburgh- Site Number : 8400018Pittsburgh, PA
More Trial Locations
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Who Is Running the Clinical Trial?
SanofiLead 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 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.
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.
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.
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.
Correction in female PKU mice by repeated administration of mPAH cDNA using phiBT1 integration system. [2017]Phenylketonuria (PKU) is a metabolic disorder secondary to a hepatic deficiency of phenylalanine hydroxylase (PAH) that predisposes affected children to develop severe and irreversible mental retardation. We have previously reported the complete and permanent correction of the hyperphenylalaninemic and hypopigmentation phenotypes in male, but not female, PKU mice after genome-targeted delivery of murine PAH (mPAH) complementary DNA (cDNA) in a phiBT1 bacteriophage integration system. Here we show that sequential administration of green fluorescent protein (GFP)- and red fluorescent protein (RFP)-expressing cassettes in the phiBT1 integration system led to distinct and non-overlapping populations of green and red fluorescent hepatocytes in vivo. The hyperphenylalaninemic and hypopigmentation phenotypes of female PKU mice were completely corrected after 10 weekly administrations of mPAH cDNA. Importantly, there was no apparent liver pathology in mice even after 10 consecutive administrations of the phiBT1 integration system. The results indicate that repeated administration of transgenes in the phiBT1 integration system can lead to their genome-targeted integration in a diverse population of hepatocytes and result in the elevation of transgene expression levels in a cumulative manner, which can be utilized to overcome insufficient transgene expression owing to low genome integration frequencies in a gene therapy paradigm for metabolic disorders.
Protective effect of recombinant adeno-associated virus 2/8-mediated gene therapy from the maternal hyperphenylalaninemia in offsprings of a mouse model of phenylketonuria. [2018]Phenylketonuria (PKU) is an autosomal recessively inherited metabolic disorder caused by a deficiency of phenylalanine hydroxylase (PAH). The accumulation of phenylalanine leads to severe mental and psychomotor retardation, and the fetus of an uncontrolled pregnant female patient presents with maternal PKU syndrome. We have reported previously on the cognitive outcome of biochemical and phenotypic reversal of PKU in a mouse model, Pahenu2, by the AAV serotype 2-mediated gene delivery of a human PAH transgene. However, the therapeutic efficacy had been limited to only male PKU mice. In this study, we generated a pseudotyped recombinant AAV2/8-hPAH vector and infused it into female PKU mice through the hepatic portal vein or tail vein. Two weeks after injection, complete fur color change to black was observed in female PKU, as in males. The PAH activity in the liver increased to 65-70% of the wild-type activity in female PKU mice and to 90% in male PKU mice. Plasma phenylalanine concentration in female PKU mice decreased to the normal value. In addition, the offsprings of the treated female PKU mice can rescue from the harmful effect of maternal hyperphenylalaninemia. These results indicate that recombinant AAV2/8-mediated gene therapy is a potential therapeutic strategy for PKU.
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 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.