Target. Modulate. Heal: Small Nucleic Acid Therapeutics and Gene Therapy Powered by Humanized Mouse Models

Lp(a) is a cholesterol-rich particle structurally similar to LDL, distinguished by the presence of apo(a), which is encoded by the LPA gene. Elevated Lp(a) levels are a recognized risk factor for cardiovascular disease. While conventional lipid-lowering therapies have limited effect on Lp(a), emerging siRNA treatments—such as olpasiran—can selectively silence hepatic LPA expression, reducing apo(a) production and significantly lowering plasma Lp(a) levels (Kronenberg et al. 2022).

In vivo efficacy of an olpasiran analog in humanized B-hLPA mice. A single dose of the olpasiran analog reduced plasma apo(a) levels by over 80% in heterozygous B-hLPA mice. These models provide a robust platform for preclinical evaluation of LPA-targeted nucleic acid therapies.

Case Study for Obesity and Type 2 Diabetes: INHBE Humanized Mice (B-hINHBE Mice)

Efficacy study of INHBE-siRNA in humanized B-hINHBE mice with high-fat diet (HFD) induced obesity. B-hINHBE mice (7 weeks, male) were fed a high-fat diet for 12 weeks to induce mice obesity. Administration of INHBE-targeting siRNA resulted in significant reductions in body weight, as well as liver triglyceride and cholesterol levels. STD (Standard Chow Diet); TA (Test Article); TG (Triglyceride); TC (Total Cholesterol).

INHBE-siRNA treatment reverses obesity phenotypes in HFD-induced humanized B-hINHBE mice. Efficacy of INHBE-targeting siRNA was evaluated in B-hINHBE humanized mice subjected to a high-fat diet (HFD). After 13 treatments, lean and adipose tissue distribution was assessed using micro-CT.

Case Study for Neurological Disease: TFR1/DMPK Humanized Mice (B-hTFR1/hDMPK Mice)

Myotonic dystrophy type 1 (DM1) is a progressive neuromuscular disorder caused by toxic RNA from CTG repeat expansion in the DMPK gene. Antibody–oligonucleotide conjugates (AOCs) deliver siRNAs to affected tissues, with transferrin receptor 1 (TfR1) serving as an effective target for muscle-specific delivery due to its high expression in skeletal muscle (Pascual-Gilabert et al. 2021).

The inhibitory efficiency of the AOC drug against human DMPK in heterozygous B-hTFR1/hDMPK mice. The human DMPK mRNA in the treatment groups (AOC) were significantly reduced compared to the control groups (naked antibody and PBS) in tibialis anterior muscle, demonstrating that B-hTFR1/hDMPK mice provide a powerful preclinical model for in vivo evaluation of human DMPK targeted AOC drug. 

Gene Therapy

Gene therapy involves the direct modification of a patient's genes to treat or prevent diseases. Techniques include replacing faulty genes, inactivating malfunctioning ones, or introducing new genes to combat disease. Biocytogen has developed a suite of gene-edited mouse models that replicate the genetic alterations found in various disorders, facilitating the evaluation and acceleration of gene therapies for conditions like:

• Duchenne Muscular Dystrophy (DMD)

• Inherited Retinal Diseases (RHO mutation)

• Hemophilia

Case Study for Duchenne Muscular Dystrophy (DMD) Gene Therapy: Humanized DMD Mice (B-hDMD (exon44-46, del45) Mice) 

Duchenne muscular dystrophy (DMD) is a severe, progressive genetic disorder caused by mutations in the DMD gene, which eliminate the production of dystrophin, a protein vital for muscle fiber stability. Without dystrophin, muscles are highly susceptible to damage, leading to gradual muscle weakness, loss of mobility, and impaired respiratory and cardiac function. Despite improved care, DMD remains a life-limiting condition with premature mortality (D'Ambrosio et al. 2023) ​​​​.

Current and investigational therapies for DMD (D'Ambrosio et al. 2023) & models available at Biocytogen

Muscle damage and histopathology in humanized B-hDMD (Exon44–46, del45) mice. A. Creatine kinase activity was significantly greater in homozygous B-hDMD (exon44-46, del45) mice compared to that in wild-type mice. B. H&E-stained muscle from B-hDMD (exon44–46, del45) mice shows dystrophic features of inflammation (red arrow) and centrally-located nuclei (black arrow), unlike normal wild-type controls.

Explore Biocytogen's Humanized Mouse Models for Small Nucleic Acid Therapeutics & Gene Therapy!