siRNAgen Therapeutics Corporation focuses on the discovery and development of RNAi therapeutics through its own innovative SAMiRNA™ tech to maximize efficacy and minimize adverse effect
Our flagship drug: SAMiRNA-AREG (amphisiran)
*Amphisiran (SAMiRNA-AREG): is oligonucleotide DNA/RNA heteroduplex nanoparticles with hydrophilic PEG and hydrophobic hydrocarbon conjugation tail at each end targeting human amphiregulin-mRNA.
Reduced Areg (Amphiregulin) cellular synthesis leads to inhibition not only of EGFR cascade & TGF-β downstream crosstalk cellular pathway, but also juxtacrine (cell to cell) proliferative signaling pathway, resulting in anti-fibrotic & anti-proliferative effects.
Anti-fibrotics: Amphisiran™ knocks down AREG(amphiregulin), which stimulates fibroblast proliferation and myofibroblast trasformation not only from the surface EGFR but also downstream pathways.
Amphiregulin (AREG) is a ligand of the epidermal growth factor receptor (EGFR), a widely expressed transmembrane tyrosine kinase, and a paracrine substance, with which engage in juxtacrine signaling synthesized as a membrane-anchored precursor protein. Alternatively, after proteolytic processing by cell membrane proteases, mainly TACE/ADAM17, AREG is secreted and behaves as an autocrine or paracrine factor. AREG gene expression and release is induced by a plethora of stimuli including inflammatory lipids, cytokines, hormones, growth factors and xenobiotics. Through EGFR binding AREG activates major intracellular signaling cascades governing cell survival, proliferation and motility. Physiologically, AREG plays an important role in the development and maturation of mammary glands, bone tissue and oocytes. Chronic elevation of AREG expression is increasingly associated with different pathological conditions, mostly of inflammatory and/or neoplastic nature.
Amphiregulin
Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease characterized by worsening lung function and dyspnea
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Radiation-induced pulmonary fibrosis (RIPF) is a side effect of lung damage caused by radiation therapy for lung cancer and breast cancer. Pathological characterization of RIPF includes excessive accumulation of extracellular matrix and myofibroblasts with scar formation, leading to disruption of pulmonary function.
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M.O.A of Amphisiran in mitigating ARDS development from COVID-19 induced ALI.
Amphisiran can inhibit fibroblast activation, myofibroblast differentiation, provisional ECM accumulation, and inflammatory hypersecretion in fibro-proliferative phase of ARDS by knocking down cellular Amphiregulin synthesis.
Acute respiratory distress syndrome (ARDS) represents a severe and rapid form of microvascular lung injury. Traditionally, ARDS is divided into three stages in which an initial inflammatory phase is followed by fibroproliferation, during which mesenchymal cells, in particular interstitial fibroblasts, migrate, replicate, and secrete extracellular matrix proteins such as collagen. Unabated, this process can lead to established interstitial and intra alveolar fibrosis, the final phase.
The fibroproliferative phase of acute respiratory distress syndrome (ARDS) has traditionally been regarded as a late event but recent studies that suggest fibroproliferation is an early response to lung injury and an important therapeutic target. The fibroblast is considered to be the major cell responsible for collagen synthesis in the lung and there is now considerable evidence to suggest that soluble mediators play a key role in fibroblast activation. (Fibroproliferation Occurs Early in the Acute Respiratory Distress Syndrome and Impacts on Outcome. American Journal of Respiratory and Critical Care Medicine. https://doi.org/10.1164/ajrccm.162.5.2001061) These include classical growth factors such as transforming growth factor-β1and proinflammatory cytokines, which had been reduced greatly by amphisiran administration in our preclinical studies.
Diabetic Kidney Disease (Diabetic nephropathy) is kidney damage that results from having diabetes. Having high blood glucose levels due to diabetes can damage the part of the kidneys that filters your blood. The damaged filter becomes 'leaky' and lets protein into your urine.
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Nonalcoholic steatohepatitis (NASH) is liver inflammation and damage caused by a buildup of fat in the liver and can get worse and cause scarring of the liver, which leads to cirrhosis. But the disease doesn't always get worse.
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Senile Erectile Dysfunction
Reactive fibrotic Heart Failure
Psoriasis
Atopy
Amphisiran is effectively knocks down amphiregulin (which plays major role in cancer cell invasion and proliferation through cell to cell exosomal release) synthesis at mRNA level.
Radiation-induced pulmonary fibrosis (RIPF) is a side effect of lung damage caused by radiation therapy for lung cancer and breast cancer. Pathological characterization of RIPF includes excessive accumulation of extracellular matrix and myofibroblasts with scar formation, leading to disruption of pulmonary function.
amphiregulin
Anti-proliferative effect of SAMiRNA-Areg will be explored on monoclonal antibody chemo-drug resistant, co-administering and mitigating acquired resistance and hostile TME.
SAMiRNA-Areg showed superb anti-fibrotic effect in various animal models and extremely low toxicity without any off-target effects in GLP tox study.
Additionally, it has good potential to be an anti-proliferative for cancer therapy as a sole and/or adjuvant agent, given the facts that amphiregulin exosomes increase cancer cell invasion and Areg (amphiregulin) also present in the tumor microenvironment (TME), which contributes to drug resistance.
Given the facts that current monoclonal antibody (anti-proliferative) cancer drugs, eg Herceptin, have been not only shown to cause serious adverse effects, but also to develop drug resistance after continuous administration, by which cause alternative and downstream pathway potentiation, SAMiRNA-Areg is a promising substitute for this kind of cancer drugs in terms of inhibiting those pathways and “body-friendly’ nature of SAMiRNA (do not block our body’s own growth factor receptor forcefully, instead precisely targeting problematic protein synthesis at DNA level).
AREG plays key role in fibrosis by stimulating myofibroblast differentiation and proliferation. It also involved in the cancer metastasis. SAMiRNA-AREG selectively delivered to inflamed fibrotic tissue and/or cancer tissue and knock down AREG mRNA more than 50% without innate immune stimulation.
Amphisiran is self-micelle-forming nanoparticle being composed of a passenger strand with hydrophobic and hydrophilic conjugate-ligands at each end, and phosphorylated guide strand in the middle. SAMiRNA spontaneously forms nanoparticle by hydrophobic ligand-interaction and also spontaneously being cleaved by hydrophobic ligand at cell-entering.
Amphisiran (FIC amphiregulin-targeting siRNA drug), which has anti-fibrotic and anti-proliferative effect with minimal adverse effect, is entering phase I stage with indication for IPF in 2020 and phase II study will be commencing in 2021 for the indication of RIPF (Radio Induced Pulmonary Fibrosis) aiming “orphan” drug designation from FDA after showing far better efficacy and toxicity profile than any other current (or under-developing) drugs in our pre-clinical studies including IPF, CKD, NASH.
We are expecting that SAMiRNA-AREG not only mitigate RIPF, but also prevent cancer- metastasis and -drug resistance as well. Thus, most of cancer patients will get benefits from it.
Indications | Key fx | |
AB-01 | Hypertrophied scar inc Keloid | *20B USD market |
AB-02 | Acne scar/Enlg pores | *New market (Anti-ageing) |
AB-03 | ILD inc IPF & RIPF | * “Orphan” for IPF & RIPF |
AB-04 | RIF (connective tissue) | *FIC(First in class) Mandatory tx before Radio Therapy |
Indications | Key fx | |
AB-05 | DNP(newly developed glomerular capillary hypertension and hyperfiltration among diabetic nephropathy with high Areg pts). | *FIC for prevention of CKD
(Slow down GFB destruction). *Companion S/Urinary Areg Diagnostics Urine Areg = prognostic to CKD & monitoring Tx response |
AB-06 | NASH | *Hindering fibrotic transformation of HSC |
AB-07 | ARDS | *”Breakthrough” for ARDS odds reduction of 28D mortality in ICU |
AB-08 | Breast Cancer (HER2+) with high Areg | *50% Br Ca pts show high Areg Will increase Herceptin sale X3(suscep, TME & resistance) |
AB-09 | NSCLC | *Prevention of bony mets & Reduce A/E |