Gene Therapy for Phenylketonuria

Recruiting at 2 trial locations

Overseen By Study Contact

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: NGGT INC.

Must not be taking: Kuvan, Palynziq

Disqualifiers: Non-PAH PKU, Liver disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 6

Duration: 1 day

12 Participants Needed

Trial Summary

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. ^{1 2 3 4 5}

Is 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. ^{1 6 7 8 9}

How 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. ^{5 10 11 12 13}

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.

Eligibility 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 haven't responded well to treatments like Kuvan or Playnzip.

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

Treatment Details

Interventions

• NGGT002

Trial Overview 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.

Participant Groups

Group I: NGGT002 Experimental Treatment 1 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.

Who Is Running the Clinical Trial?

NGGT INC.

Lead Sponsor

Trials

1

Recruited

10+

NGGT (Suzhou) Biotechnology Co., Ltd.

Lead Sponsor

Trials

3

Recruited

40+

Findings from Research

The study demonstrated that using a synthetic AAV vector (Anc80) to deliver a functional copy of the PAH gene in a mouse model of PKU resulted in a significant and lasting reduction of phenylalanine levels, indicating effective restoration of metabolic function.

Administration of the AAV vector was safe, with no serious adverse effects observed even at the highest tested dose, and only minor, transient changes in liver enzymes, suggesting a promising approach for gene therapy in PKU.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of an adeno-associated virus serotype Anc80 to provide durable cure of phenylketonuria in a mouse model. Kaiser, RA., Weber, ND., Trigueros-Motos, L., et al.[2022]

AAV8-PAL gene therapy effectively corrected high phenylalanine levels in both male and female PKU mice, demonstrating long-term efficacy after a single intravenous treatment.

The therapy showed no significant liver injury, indicating a safe approach for potential treatment of phenylketonuria (PKU) in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Metabolic Correction of Phenylketonuria by AAV-Delivered Phenylalanine Amino Lyase. Tao, R., Xiao, L., Zhou, L., et al.[2022]

Phenylketonuria (PKU) is a genetic disorder caused by mutations in the phenylalanine hydroxylase gene, leading to harmful levels of phenylalanine in the body, which can result in severe mental and behavioral issues if untreated.

Current treatment involves a strict low-protein diet and amino acid supplementation, but despite good clinical outcomes, patients still experience neuropsychological deficits, highlighting the need for new therapies like tetrahydrobiopterin supplementation and potential future options such as gene therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phenylketonuria: a 21st century perspective. van Spronsen, FJ.[2021]

Gene therapy using a recombinant adenoviral vector to deliver the human PAH gene effectively normalized phenylalanine levels in PAH-deficient mice within one week, showcasing the potential for treating classical phenylketonuria (PKU).

The study found that achieving only 10-20% of normal PAH enzyme activity in the liver was enough to restore normal serum phenylalanine levels, indicating that even partial restoration of enzyme function could be therapeutically beneficial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy for phenylketonuria: phenotypic correction in a genetically deficient mouse model by adenovirus-mediated hepatic gene transfer. Fang, B., Eisensmith, RC., Li, XH., et al.[2012]

A gene therapy using a recombinant adeno-associated virus (rAAV) vector successfully normalized blood phenylalanine levels in a PKU mouse model, demonstrating significant long-term efficacy without toxicity or immune response.

This approach achieved complete correction of hyperphenylalaninemia in both male and female mice, suggesting that a single intravenous injection could be a promising future treatment for PKU patients, overcoming limitations of current dietary restrictions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Ding, Z., Georgiev, P., Thöny, B.[2013]

Pegylated phenylalanine ammonia lyase (PAL) shows promise as a treatment for phenylketonuria (PKU) by effectively lowering blood phenylalanine levels in mouse models, offering a potential alternative to the difficult low-phenylalanine diet.

This modified PAL has improved properties, including better activity, longer-lasting effects, and reduced immune response, making it a more viable option for sustained treatment in PKU patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phenylalanine ammonia lyase, enzyme substitution therapy for phenylketonuria, where are we now? Sarkissian, CN., Gámez, A.[2013]

In a study using the Pah(enu2/enu2) PKU mouse model, an oral enzyme substitution therapy with a modified phenylalanine ammonia lyase (PAL) significantly reduced plasma phenylalanine levels by approximately 40%, demonstrating its efficacy (p=0.0029).

The reduction in phenylalanine was dose- and loading-dependent, suggesting that more frequent and smaller doses could enhance treatment effectiveness, making oral PAL therapy a promising adjunct to dietary management for patients with phenylketonuria.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of orally administered PEGylated phenylalanine ammonia lyase in mice for the treatment of Phenylketonuria. Sarkissian, CN., Kang, TS., Gámez, A., et al.[2022]

Alipogene tiparvovec (Glybera) has been approved in Europe as a significant advancement in gene therapy for treating familial lipoprotein lipase deficiency, marking a milestone in the clinical application of gene therapies.

The review highlights important safety considerations for gene therapies using adeno-associated virus (AAV) vectors, including potential acute and immunological reactions, viral distribution, and risks of DNA integration and carcinogenicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety profile of recombinant adeno-associated viral vectors: focus on alipogene tiparvovec (Glybera®). Salmon, F., Grosios, K., Petry, H.[2014]

Recombinant phenylalanine ammonia-lyase (PAL) from parsley, when chemically modified with PEG, showed improved stability in circulation and effectively reduced plasma phenylalanine levels in mice, suggesting its potential as a treatment for phenylketonuria (PKU).

This approach addresses the challenges of low stability and antigenicity associated with plant-derived enzymes, making PEG-PAL a promising therapeutic option for individuals with PKU who need to manage elevated phenylalanine levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phenylalanine ammonia-lyase modified with polyethylene glycol: potential therapeutic agent for phenylketonuria. Ikeda, K., Schiltz, E., Fujii, T., et al.[2018]

Phenylketonuria (PKU) affects about 1 in 16,000 live births in North America and requires lifelong dietary restrictions and supplementation, which can be difficult to maintain and lead to serious health issues if not followed.

Current research is focusing on developing more permanent solutions for PKU, such as cell transplantation and gene therapy, to potentially cure the disease rather than relying solely on dietary management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Progress toward cell-directed therapy for phenylketonuria. Harding, C.[2021]

Gene therapy using adeno-associated viruses (AAVs) to deliver the phenylalanine hydroxylase (PAH) enzyme has shown effective and sustained clearance of phenylalanine (Phe) in mice for over a year, indicating a potential long-term treatment for phenylketonuria (PKU).

Combining PAH gene therapy with supplementation or gene therapy for tetrahydrobiopterin (BH(4)) in skeletal muscle resulted in significant and lasting reductions in blood Phe levels, suggesting a dual approach could be a viable alternative to the strict dietary restrictions currently required for PKU patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term correction of murine phenylketonuria by viral gene transfer: liver versus muscle. Thöny, B.[2021]

Long-term enzyme substitution therapy in adults with phenylketonuria (PKU) has shown unexpected improvements in neuropsychiatric outcomes, suggesting a potential shift in treatment perspectives for this condition.

Various gene therapy approaches, including rAAV vectors and genome editing, have successfully targeted the liver in mouse models of PKU, indicating promising avenues for future human gene therapy applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

State-of-the-Art 2019 on Gene Therapy for Phenylketonuria. Grisch-Chan, HM., Schwank, G., Harding, CO., et al.[2023]

Infusing a recombinant adenoviral vector that expresses the human PAH gene into the portal circulation of PAH-deficient mice can restore 10-80% of normal liver PAH activity and normalize serum phenylalanine levels, indicating a promising approach for treating classical phenylketonuria (PKU).

While the effects of this gene therapy are currently temporary and re-administration does not enhance the outcome, the results suggest that with the development of more persistent gene delivery systems, PKU could potentially be fully corrected through somatic gene therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy for phenylketonuria. Eisensmith, RC., Woo, SL.[2019]

References

1. United States pubmed.ncbi.nlm.nih.gov

Use of an adeno-associated virus serotype Anc80 to provide durable cure of phenylketonuria in a mouse model. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Long-Term Metabolic Correction of Phenylketonuria by AAV-Delivered Phenylalanine Amino Lyase. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Phenylketonuria: a 21st century perspective. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Gene therapy for phenylketonuria: phenotypic correction in a genetically deficient mouse model by adenovirus-mediated hepatic gene transfer. [2012]

5. England pubmed.ncbi.nlm.nih.gov

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]

6. United States pubmed.ncbi.nlm.nih.gov

Phenylalanine ammonia lyase, enzyme substitution therapy for phenylketonuria, where are we now? [2013]

7. United States pubmed.ncbi.nlm.nih.gov

Evaluation of orally administered PEGylated phenylalanine ammonia lyase in mice for the treatment of Phenylketonuria. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Safety profile of recombinant adeno-associated viral vectors: focus on alipogene tiparvovec (Glybera®). [2014]

9. Austria pubmed.ncbi.nlm.nih.gov

Phenylalanine ammonia-lyase modified with polyethylene glycol: potential therapeutic agent for phenylketonuria. [2018]

10. Denmark pubmed.ncbi.nlm.nih.gov

Progress toward cell-directed therapy for phenylketonuria. [2021]

11. United States pubmed.ncbi.nlm.nih.gov

Long-term correction of murine phenylketonuria by viral gene transfer: liver versus muscle. [2021]

12. United States pubmed.ncbi.nlm.nih.gov

State-of-the-Art 2019 on Gene Therapy for Phenylketonuria. [2023]

13. Norway pubmed.ncbi.nlm.nih.gov

Gene therapy for phenylketonuria. [2019]