mRNA-3927 for Propionic Acidemia

Recruiting at23 trial locations

Age: Any Age

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: ModernaTX, Inc.

Disqualifiers: Organ transplant, Heart failure, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial tests mRNA-3927, a new treatment using messenger RNA, in people with propionic acidemia, a rare genetic disorder. The treatment helps the body make a missing protein to improve health. The study aims to find the best dose and check its safety and effectiveness.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.

How does the drug mRNA-3927 differ from other treatments for propionic acidemia?

mRNA-3927 is unique because it uses messenger RNA (mRNA) technology to potentially address the underlying genetic cause of propionic acidemia by providing instructions to produce the missing or defective enzyme, propionyl-CoA carboxylase, which is not targeted by traditional treatments. ^{1 2 3 4 5}

Research Team

Eligibility Criteria

This trial is for people aged 1 year and older with a genetic confirmation of propionic acidemia (PA). Participants must have had at least one metabolic decompensation event in the past year. They can't join if they have severe heart failure, organ transplants, certain heart rhythm issues, recent COVID-19 vaccination, or poor kidney function.

Inclusion Criteria

I have been diagnosed with PA through genetic testing.

I am 8 years or older and could be one of the first two participants.

In the year before signing up, you have been diagnosed with at least one major depressive episode.

Exclusion Criteria

I received my last COVID-19 vaccine or booster within the last 6 weeks.

Your heart's electrical activity takes longer than normal to reset after each beat.

I have had an organ transplant or plan to have one during the study.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Predosing Observational Period

Participants undergo observation before receiving the treatment

2 weeks

Dose Optimization (Part 1)

Participants (≥1 year of age) receive mRNA-3927 by IV infusion every 2 or 3 weeks for up to 10 doses to determine optimal dosing

20-30 weeks

10 visits (in-person)

Dose Expansion (Part 2)

Additional participants (≥1 year of age) receive mRNA-3927 by IV infusion every 2 weeks for up to 12 months to further characterize safety and efficacy

12 months

24 visits (in-person)

Infant Evaluation (Part 3)

Infants (<1 year of age) receive mRNA-3927 by IV infusion every 2 weeks for up to 12 months to evaluate safety and efficacy

12 months

24 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• mRNA-3927 (RNA Therapy)

Trial Overview The study tests mRNA-3927's safety and effectiveness in treating PA. It has two parts: first to find a safe dose that works (Dose Optimization), then to further assess this dose's efficacy and safety (Dose Expansion) by monitoring biomarkers.

Participant Groups

Group I: Part 1 (Dose Optimization), Part 2 (Dose Expansion), and Part 3 (Infants) Experimental Treatment 1 Intervention

Part 1 (Dose Optimization): Participants (≥1 year of age) will receive single dose of mRNA-3927 by intravenous (IV) infusion every 2 weeks (Q2W) or every 3 weeks (Q3W) for up to 10 doses. Part 2 (Dose Expansion): Participants (≥1 year of age) will receive single dose of mRNA-3927 (identified during Dose Optimization Phase) by IV infusion Q2W for up to 12 months. Part 3: Participants (\<1 year of age) will receive single dose of mRNA-3927 (identified during Dose Optimization Phase) by IV infusion Q2W for up to 12 months.

Who Is Running the Clinical Trial?

ModernaTX, Inc.

Lead Sponsor

Trials

127

Recruited

66,790,000+

Dr. Stephen Hoge

ModernaTX, Inc.

Chief Medical Officer

MD from Harvard Medical School

Stéphane Bancel

ModernaTX, Inc.

Chief Executive Officer since 2011

MBA from Harvard Business School, MSc in Engineering from École Centrale Paris

Findings from Research

A new method has been developed to identify defective genes causing propionic acidemia by using lipid-mediated transient transfection of normal PCCA or PCCB genes into primary fibroblasts.

This approach allows for reliable identification of the specific gene mutation responsible for the enzyme defect, aiding in the mutational analysis of propionyl-CoA carboxylase.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transfection screening for defects in the PCCA and PCCB genes encoding propionyl-CoA carboxylase subunits. Rodriguez-Pombo, P., Pérez-Cerdá, C., Desviat, LR., et al.[2019]

Seven novel splicing mutations in the PCCA and PCCB genes were identified in patients with propionic acidemia, primarily among individuals of Central Asian descent, indicating potential founder effects.

Functional analysis of these mutations revealed that they disrupt normal splicing of the propionyl-CoA carboxylase enzyme, leading to a complete absence of normally spliced transcripts, which emphasizes the importance of transcript analysis alongside genomic sequencing for understanding the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New splicing mutations in propionic acidemia. Desviat, LR., Clavero, S., Perez-Cerdá, C., et al.[2020]

In a study of 11 Chinese patients with propionic acidemia, researchers identified 13 mutations in the PCCA and PCCB genes, including 10 novel mutations, which contribute to the disease's genetic diversity.

The study found no predominant mutation among the patients, indicating a varied mutation spectrum in the Chinese population affected by propionic acidemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Gene mutation analysis in patients with propionic acidemia]. Hu, YH., Han, LS., Ye, J., et al.[2019]

A study screening over 130,000 Japanese newborns revealed that the frequency of propionic acidemia is more than ten times higher than previously reported, with many patients exhibiting milder symptoms than the severe form typically associated with the condition.

The research identified a common mutation (Y435C) in the PCCB gene among patients with milder phenotypes, highlighting the importance of recognizing these patients to understand their natural history and the diverse effects of PCCB mutations, including unusual patterns of exon skipping and mRNA absence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Unexpectedly high prevalence of the mild form of propionic acidemia in Japan: presence of a common mutation and possible clinical implications. Yorifuji, T., Kawai, M., Muroi, J., et al.[2022]

Two mutations in the PCCB gene were identified in a patient with propionic acidemia, highlighting the genetic complexity of this metabolic disorder.

One mutation caused a deletion of an isoleucine residue, while the other resulted in a frameshift and a premature stop codon, indicating that both mutations significantly impair the function of the propionyl-CoA carboxylase enzyme.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two distinct mutations at the same site in the PCCB gene in propionic acidemia. Lamhonwah, AM., Troxel, CE., Schuster, S., et al.[2019]

References

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

Transfection screening for defects in the PCCA and PCCB genes encoding propionyl-CoA carboxylase subunits. [2019]

2. England pubmed.ncbi.nlm.nih.gov

New splicing mutations in propionic acidemia. [2020]

3. China pubmed.ncbi.nlm.nih.gov

[Gene mutation analysis in patients with propionic acidemia]. [2019]

4. Germany pubmed.ncbi.nlm.nih.gov

Unexpectedly high prevalence of the mild form of propionic acidemia in Japan: presence of a common mutation and possible clinical implications. [2022]

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

Two distinct mutations at the same site in the PCCB gene in propionic acidemia. [2019]