NANO-GENE-THERAPY

Many solid tumors, such as pancreatic ductal adenocarcinoma (PDAC), hepatocellular carcinoma (HCC), prostate adenocarcinoma (PAC), non-small cell lung cancer (NSCLC) and certain breast cancer, are characterized by a highly dense fibrotic stroma termed “desmoplasia”, which impedes the penetration of most small molecules, antibodies, and immune cells. Nanoparticle formulation is a clinically validated approach to facilitate drug penetration in desmoplastic cancers. For instance, liposome-encapsulated irinotecan (Onivyde, Ipsen Biopharm) extends the survival of patients with PDAC and has become the only FDA-approved second-line treatment.

 

Lipid nanoparticle (LNP)-formulated small interfering RNA (siRNA) therapeutics have recently emerged as a safe and efficient approach in the molecular targeting of disease driver genes. siRNA is advantageous over microRNA as a gene therapy agent due to its gene-specific silencing effect (Table 1). Parenterally administration of an LNP-encapsulated siRNA specific for transthyretin (Patisiran, Alnylam Pharmaceuticals) has been shown to reduce up to 86.8% of transthyretin produced by the liver in patients with hereditary transthyretin-mediated amyloidosis and thus became the first clinically approved RNAi drug. Antapodia Nanotherapeutics leverages tissue-customized LNP carriers to deliver invadopodia-targeted siRNA to liver cancer or non-liver desmoplastic cancers, resulting in tremendous anti-tumor and anti-metastasis efficacies in preclinical studies. The company is working with academic and industrial leaders to enhance the packaging efficacy and tumor-targeting properties of nanoparticles to further improve the treatment efficacy of its nano-gene-therapy products.

Table 1. The advantages of using siRNA as a gene-therapy agent

 

Identifying disease driver gene

Number of target genes

Specificity

Silencing efficacy

Clinical off-target effect

Clinical approval

siRNA

Necessary

1

High

Can to optimized to > 95%

Very low

Yes1

microRNA

Unnecessary

> 100

Low-to-medium

Varies with target genes

Frequent

No

 

1. ONAPATTRO® (patisiran) has been approved for the treatment of hereditary transthyretin-mediated amyloidosis in August, 2018.

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