Gene Therapy for Phenylketonuria

Recruiting at 3 trial locations

Overseen By Trial Specialist

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: BioMarin Pharmaceutical

Disqualifiers: Bh4 deficiency, Liver dysfunction, Malignancy, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Single administration

100 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, you must avoid substances that can harm the liver after receiving the treatment.

What data supports the effectiveness of the treatment BMN 307 for phenylketonuria?

Research shows that gene therapy using viral vectors, like adeno-associated viruses (AAVs), can effectively lower phenylalanine levels in mice with phenylketonuria (PKU) for over a year. This suggests that similar gene therapy approaches, like BMN 307, could potentially be effective for treating PKU in humans. ^{1 2 3 4 5}

Is gene therapy for phenylketonuria safe in humans?

Research on gene therapy for phenylketonuria in mice shows it is generally safe, with no significant liver damage or other adverse effects observed, even at high doses. These findings suggest that the treatment could be safe for humans, but more studies are needed to confirm this. ^{1 3 4 6 7}

How does the treatment BMN 307 differ from other treatments for phenylketonuria?

BMN 307 is a gene therapy that uses a viral vector to deliver a functional copy of the phenylalanine hydroxylase (PAH) gene to the liver, aiming to correct the underlying genetic cause of phenylketonuria. This approach is unique because it targets the root cause of the disorder, potentially offering a long-term solution, unlike current treatments that require strict dietary management. ^{1 3 4 8 9}

What is the purpose of this trial?

This is a Phase 1/2, open-label, dose escalation study to evaluate the safety, efficacy and tolerability of BMN 307 in adult PKU subjects with PAH deficiency. Participants will receive a single administration of BMN 307 and will be followed for safety and efficacy.

Research Team

Medical Director, MD

Principal Investigator

BioMarin Pharmaceutical

Eligibility Criteria

This trial is for adults with Phenylketonuria (PKU), a condition where the body can't break down an amino acid called phenylalanine due to PAH deficiency. Participants must have high levels of phenylalanine in their blood and be willing to maintain their current diet, avoid liver-damaging substances, use contraception, and follow study rules.

Inclusion Criteria

Ability and willingness to maintain dietary protein intake consistent with baseline intake

I am willing and able to follow the study's procedures and requirements.

I am willing to avoid liver-damaging substances after treatment.

Exclusion Criteria

I have previously undergone gene therapy.

Any condition that, in the opinion of the investigator or Sponsor, would prevent the subject from fully complying with the requirements of the study

I have had cancer before.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single administration of BMN 307

Single administration

Follow-up

Participants are monitored for safety and efficacy after treatment

12 months

Treatment Details

Interventions

• BMN 307

Trial Overview The trial tests BMN 307, a gene therapy intended to correct the genetic defect causing PKU. It's given once to see if it's safe and effective at lowering phenylalanine levels. The study gradually increases doses among participants who are closely monitored over time.

Participant Groups

Group I: Dose 3 of BMN 307 Experimental Treatment 1 Intervention

Group II: Dose 2 of BMN 307 Experimental Treatment 1 Intervention

Group III: Dose 1 of BMN 307 Experimental Treatment 1 Intervention

Who Is Running the Clinical Trial?

BioMarin Pharmaceutical

Lead Sponsor

Trials

162

Recruited

115,000+

Alexander Hardy

BioMarin Pharmaceutical

Chief Executive Officer since 2023

MBA from INSEAD

Greg Friberg

BioMarin Pharmaceutical

Chief Medical Officer

MD from New York Medical College

Findings from Research

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]

In female PKU mice, the administration of mPAH cDNA using a phiBT1 bacteriophage integration system completely corrected the hyperphenylalaninemic and hypopigmentation phenotypes after 10 weekly treatments, demonstrating the efficacy of this gene therapy approach.

The study found no liver pathology in the mice even after multiple administrations, indicating that this method is safe for repeated use in gene therapy for metabolic disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Correction in female PKU mice by repeated administration of mPAH cDNA using phiBT1 integration system. Chen, L., Woo, SL.[2017]

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]

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]

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]

References

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

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

2. France pubmed.ncbi.nlm.nih.gov

[Phenylketonuria, from diet to gene therapy]. [2023]

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

Correction in female PKU mice by repeated administration of mPAH cDNA using phiBT1 integration system. [2017]

4. 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]

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

State-of-the-art 2023 on gene therapy for phenylketonuria. [2023]

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

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

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

Long-term enzymatic and phenotypic correction in the phenylketonuria mouse model by adeno-associated virus vector-mediated gene transfer. [2013]

8. Norway pubmed.ncbi.nlm.nih.gov

Gene therapy for phenylketonuria. [2019]

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

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