ALN-4324 / Alnylam - LARVOL DELTA

SINGLE-NUCLEUS RNA SEQUENCING OF FFPE HUMAN LIVER TISSUE IDENTIFIES ZONE-SPECIFIC EXPRESSION PATTERNS OF MASLD-ASSOCIATED GENES (AASLD 2026) - "PNPLA3, GCKR, GPAM, INSR, SREBF1, and TM6SF2 were broadly upregulated, whereas FTO, GRB14, and TRIB1 were consistently downregulated across hepatocyte zones... We established a human liver FFPE snRNA-seq cohort spanning MASLD stages and mapped the cell-type and zone-specific expression patterns of MASLD GWAS genes. Our findings suggest spatially distinct roles for GWAS identified MASLD genes. Our future work will integrate a spatial transcriptomics cohort to interpret the local biology of these genes."

Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • ADH1B • APOE • FTO • IR • PNPLA3 • SREBF1 • TRIB1

IS MASLD PART OF CARDIOVASCULAR-KIDNEY-METABOLIC SYNDROME? GENETIC EVIDENCE FOR A CAUSAL, METABOLICALLY-MEDIATED CKM-TO-ALT EFFECT (AASLD 2026) - "However, a smaller insulin-resistance and atherogenic-dyslipidemia cluster, including IRS1, GRB14, MSL2, and SH2B3, showed a stronger effect on cALT... Genetically predicted CKM is associated with higher ALT, consistent with a causal effect driven primarily by insulin-resistance/ atherogenic-dyslipidemia variants, with a discordant cluster showing an inverse effect. These data establish a strong, metabolically mediated CKM-to-ALT genetic signal; analyses formally testing MASLD's inclusion in CKM are ongoing."

Cardiovascular • Diabetes • Dyslipidemia • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • Type 2 Diabetes Mellitus • FADS2 • SH2B3

Conflicting Molecular Hallmarks of Lipedema Reflect Cell-Composition Confounding: A Reanalysis and Germline Reframing. (PubMed, Cureus) - "Lipedema's inflammatory status is currently undecidable from composition-confounded bulk tissue rather than settled, which explains the field's contradictory literature; the germline evidence, limited by its case definitions, supports as a hypothesis an adipo-vascular and connective program rather than a primary immune lesion; and pain, not weight, should anchor trials. We specify, but do not perform, the single decisive experiment - paired thigh-versus-abdomen single-nucleus RNA-seq with explicit composition control."

Journal • Pain • NLRP3 • RSPO3

Exploration and experimental verification of triaptosis-related prognostic genes and cells in gastric cancer. (PubMed, Mol Biol Rep) - "The three-gene prognostic signature predicted GC prognosis and was associated with distinct immune and genomic features, suggesting potential value for risk stratification and personalized treatment."

Biomarker • Journal • Tumor mutational burden • Gastric Cancer • Oncology • Solid Tumor • TMB • TRG

A Study to Evaluate ALN-4324 on Insulin Sensitivity in Adults With Type 2 Diabetes Mellitus (clinicaltrials.gov) - P2 | N=24 | Recruiting | Sponsor: Alnylam Pharmaceuticals | N=40 ➔ 24

Enrollment change • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

ALN-4324-001: A Study to Evaluate ALN-4324 in Overweight to Obese Healthy Volunteers and in Overweight to Obese Patients With T2DM (clinicaltrials.gov) - P1/2 | N=105 | Active, not recruiting | Sponsor: Alnylam Pharmaceuticals | Recruiting ➔ Active, not recruiting

Enrollment closed • Diabetes • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Integrated three-dimensional genomic analysis reveals that dynamic changes in chromatin structure are associated with differences in egg production performance between White Leghorn and Wenchang chickens. (PubMed, Poult Sci) - "At the compartment level, key metabolic genes such as BBOX1 and GRB14 underwent B-to-A compartment switching and transcriptional activation in White Leghorns, which may be associated with their high laying trait...In summary, this study reveals a close correlation between the dynamic changes in the 3D chromatin structure and the transcription differences in the livers of the two chicken breeds, and these differences may be linked to egg production performance. These findings provide new insights into the genetic basis underlying the liver's role in regulating poultry laying performance."

Journal • Metabolic Disorders • ACACB • ACOX1 • ACSL1 • BBOX1 • CPT1A • DHCR7 • EHHADH • SQLE

Population Structure Analysis and Candidate Gene Screening for Twinning Trait in Simmental Cattle. (PubMed, Animals (Basel)) - "Furthermore, by combining Fst and θπ analysis (comparing the Xinjiang population with other geographical populations), a total of 89 candidate genes associated with the twinning trait in Xinjiang Chinese Simmental cattle were screened, including CYP19A1, HORMAD1, GRB14, CADM2, CXCR4, and others that have been reported to be closely related to oogenesis and reproductive function. In summary, this study explores genome-wide genetic differences among Simmental cattle populations from different regions, deepens our understanding of their population structures, and offers new candidate genes and molecular markers for high-fecundity breeding in Simmental cattle."

Journal • CXCR4 • CYP19A1 • HORMAD1

tRF-3005a regulates exon skipping of SPAG4 by interacting with RALY to drive gastric cancer progression. (PubMed, Cell Death Discov) - "Mechanistically, tRF-3005a bound to RALY, enhancing its interaction with SPAG4 mRNA, suppressing exon 8 skipping and leading to an increased generation of oncogenic SPAG4-L isoforms, thereby activating GRB14/PI3K/AKT signaling and ultimately promoting GC progression. This study reveals a novel mechanism wherein tRF-3005a promotes gastric cancer development by regulating RALY-mediated alternative splicing of SPAG4 to activate the GRB14/PI3K/AKT pathway, suggesting it may serve as a prognostic biomarker and therapeutic target."

Journal • Gastric Cancer • Oncology • Solid Tumor

A Study to Evaluate ALN-4324 on Insulin Sensitivity in Adults With Type 2 Diabetes Mellitus (clinicaltrials.gov) - P2 | N=40 | Recruiting | Sponsor: Alnylam Pharmaceuticals

New P2 trial • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

ALN-4324-001: A Phase 1/2 Study to Evaluate ALN-4324 in Overweight to Obese Healthy Volunteers and in Overweight to Obese Patients With T2DM (clinicaltrialsregister.eu) - P1/2 | N=35 | Not yet recruiting | Sponsor: Alnylam Pharmaceuticals Inc.

New P1/2 trial • Diabetes • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Polystyrene and polyvinyl chloride microplastics exposure induces ocular surface inflammation by causing mitochondrial damage and lipid metabolic disruption. (PubMed, J Hazard Mater) - "Specifically, aberrant opening of the mitochondrial permeability transition pore (mPTP), leakage of mitochondrial DNA (mtDNA), and dysregulation of lipid metabolism-associated genes LIPG and GRB14 emerged as key drivers of inflammation in HCE-T cells...Notably, corneal inflammation was markedly attenuated by treatment with the mitochondria-targeted antioxidant SkQ1 and an adiponectin receptor agonist. Collectively, these findings delineate a mitochondria- and lipid metabolism-mediated mechanism for PS/PVC-induced ocular surface inflammation, offering mechanistic insights and potential therapeutic strategies for mitigating microplastic-associated ocular toxicity."

Journal • Dry Eye Disease • Inflammation • Keratitis • Metabolic Disorders • Ocular Inflammation • Ophthalmology

Uncovering the Structural Logic of Grb7: From Domain Mutagenesis to Therapeutic Implications in Cancer Signaling. (PubMed, J Mol Recognit) - "Grb7 is a member of the Grb7 protein family, which also includes Grb10 and Grb14...Truncating the distorted poly-proline region of Grb7 improved its model quality. Collectively, the results provide additional insight into the regulatory mechanisms of Grb7 and may aid in the development of Grb7-signaling dependent cancer therapeutics."

Journal • Oncology • GRB7

A Study to Evaluate ALN-4324 in Overweight to Obese Healthy Volunteers and in Overweight to Obese Patients With T2DM (clinicaltrials.gov) - P1/2 | N=144 | Recruiting | Sponsor: Alnylam Pharmaceuticals | Phase classification: P1 ➔ P1/2 | N=84 ➔ 144 | Trial completion date: Jun 2026 ➔ Aug 2027 | Trial primary completion date: Jun 2026 ➔ Aug 2027

Enrollment change • Phase classification • Trial completion date • Trial primary completion date • Diabetes • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

A Phase 1 Study to Evaluate ALN-4324 in Overweight to Obese Healthy Volunteers (clinicaltrials.gov) - P1 | N=84 | Recruiting | Sponsor: Alnylam Pharmaceuticals | Not yet recruiting ➔ Recruiting

Enrollment open • Obesity

A Phase 1 Study to Evaluate ALN-4324 in Overweight to Obese Healthy Volunteers (clinicaltrials.gov) - P1 | N=84 | Not yet recruiting | Sponsor: Alnylam Pharmaceuticals

New P1 trial • Obesity