Phase 1 trials of PNPLA3 siRNA in I148M homozygous patients with MAFLD

Fabbrini E; Rady B; Koshkina A; Jeon JY; Ayyar VS; Gargano C; DiProspero N; Wendel S; Hegge J; amilton H; Ding ZM; Afrazi M; Nicholas A; Pei T; Nakano M; Ouchi S; Saito Y; Yamashita A; Tamamura R; Salazar H; Shapiro C; Yoshihara T; Yonemura T; Inoue S; Matsuoka O; Erion M; Pocai A; Makimura H

doi:10.1530/ey.22.15.2

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ESPE Yearbook of Paediatric Endocrinology (2025) 22 15.2 | DOI: 10.1530/ey.22.15.2

ESPEYB25 15. Editors' Choice Genetics (9 abstracts)

15.2. Phase 1 trials of PNPLA3 siRNA in I148M homozygous patients with MAFLD

Fabbrini E , Rady B , Koshkina A , Jeon JY , Ayyar VS , Gargano C , DiProspero N , Wendel S , Hegge J , Hamilton H , Ding ZM , Afrazi M , Nicholas A , Pei T , Nakano M , Ouchi S , Saito Y , Yamashita A , Tamamura R , Salazar H , Shapiro C , Yoshihara T , Yonemura T , Inoue S , Matsuoka O , Erion M , Pocai A & Makimura H

N Engl J Med 2024; 391:475-476. PMID: 39083780 doi: 10.1056/NEJMc2402341

In Brief: This Phase 1 randomised controlled trial tested a single subcutaneous injection of JNJ-75220795, a siRNA (molecular inhibitor) against PNPLA3, in participants who were homozygous (n=40) or heterozygous (n=24) for the I148M genetic variant in PNPLA3. Dose-dependent reductions in liver fat content were seen in homozygous but not heterozygous participants, apparent at 6 weeks, peaked at 12 weeks (46% reduction) and sustained for at least 24 weeks. No safety issues were identified.

Comment: This successful new intervention targeting the gene, PNPLA3 (patatin-like phospholipase domain-containing 3), builds on work that originally identified PNPLA3 through a genome-wide association study (GWAS) for metabolic dysfunction-associated fatty liver disease (MASLD) (1). The PNPLA3 risk allele, I148M, disrupts enzymatic lipolysis activity on lipid droplets in hepatocytes, and thereby confers MASLD. Homozygotes for PNPLA3 I148M are more severely affected and have increased susceptibility to liver fibrosis, cirrhosis, and hepatocellular carcinoma. In previous studies, JNJ-75220795, a siRNA against PNPLA3, resulted in sustained silencing of PNPLA3 mRNA. Future studies are needed to characterise the duration of effect and optimal dosing and frequency of JNJ-75220795.

Despite well-recognised limitations of GWAS findings to pinpoint causative genes and mechanisms of disease, its use and wealth of findings continue to grow and there are increasing examples of mechanistic and treatment insights.

Reference: 1. Romeo S et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008; 40(12):1461-5. doi: 10.1038/ng.257.