PIPELINE | CV-15
Novel Anti-Viral/Anti-Inflammatory Immunotherapeutic Agent For COVID-19
The outbreak of a highly contagious pandemic known as coronavirus disease 19 (COVID-19) is caused by a novel strain of coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is known to cause infection via binding with human angiotensin convert enzyme 2 (hACE2) receptor, resulting in a hyperactivation of the natural anti-viral inflammatory immune responses essential for the self-defense and subsequently an acute overexpression of pro-inflammatory cytokines.
The elevated cytokine levels in COVID-19 patients often triggers a detrimental pathological event known as “cytokine storm”, ultimately developing into an acute respiratory distress syndrome (ARDS), defined as the presence of bilateral lung infiltrates and severe hypoxemia and even irreversible pulmonary fibrosis.
Statistical reports revealed that while 81% of patients display mild symptoms, approximately 14% experience severe cases and 5% experience fatal cases accompanied by lung injuries such as pneumonia, ARDS and eventual death.
Hence, the commonly observed ARDS, and the elevated levels of pro-inflammatory cytokines and chemokines that cause ARDS, could be regarded as the clinical hallmark for the severe cases of SARS-CoV-2 infection. COVID-19 patients in intensive care unit (ICU) showed particularly higher levels of IL-2, IL-7, IL-10, G-CSF, IP-10, MCP-1, MIP-1α and TNF-α. From these cases we can deduce that elevated cytokine levels are closely linked to COVID-19 clinical symptoms.
Previously, a polypeptide suppressing various pro-inflammatory pathways caused by infection has been developed by synthesizing the 1’st generation hydrophobic cell-penetrating peptide (CPP), termed membrane translocating sequence (MTS) derived from the signal peptide of fibroblast growth factor 4 (FGF4), along with NF-κB-derived nuclear localization sequence (NLS). This peptide was named Cell-permeable nuclear import inhibitor (CP-NI).
However, CP-NI was hard to manufacture mainly due to its low solubility, resulting in low clinical applicability. To address this limitation, improved cell-permeable nuclear import inhibitor (iCP-NI) has been developed by adopting advanced macromolecule transduction domain (aMTD) and demonstrated its superior stability and activity in sepsis animal models. Moreover, iCP-NI was introduced as a potent drug candidate to treat severe or fatal cases of COVID-19 by suppressing hyperinflammation and preventing inflammation-induced death. iCP-NI is a peptide drug designed by combining NLS with hydrophobic cell-permeable peptide (CPP), and it displays the ability to enter the cell membrane on its own without an additional guiding mechanism.
To reflect SARS-CoV-2 infection-mediated inflammation conditions, a lethal pneumonitis animal model has been developed by intratracheal administration of LPS and Poly I:C. By increasing the survivability of this lethal pneumonitis animals from 32% to 84% and reducing the expression of inflammatory cytokine and tissue destruction of lungs, iCP-NI proved its efficacy and potential as a novel COVID-19 therapeutic agent (Figure 1).
Currently, no drugs are available for COVID-19 treatment worldwide. Only individual precautions and international strategical regulations are implemented to combat the disease, without a fundamental therapeutic treatment solution.
Hence, the introduction of iCP-NI, an effective anti-inflammatory agent with a mechanism that directly blocks COVID-19-induced inflammation, could revolutionize our combat against the disease. The potential of iCP-NI as a novel therapeutic agent against COVID-19 is clearly demonstrated in this study, proving its working mechanism as well as remarkable in vivo therapeutic efficacy.
Figure 1. iCP-NI proved its potential as a novel COVID-19 therapeutics by reducing mortality rate of animals up to 79.6% in LPS/Poly I:C-induced severe pneumonitis model
PIPELINE | CV-15
iCP-NI, Inflammatory Bowel Disease
A Powerful Pro-Inflammatory Cytokine Blocker, iCP-NI For Incurable Inflammatory Bowel Disease (IBD) That Reduces Quality Of Life In Modern Society
Inflammatory bowel disease (IBD) including ulcerative colitis and Crohn's disease, describes a group of incurable & chronic autoimmune disease (AID) in which the gastrointestinal (GI) tract become severely inflamed with uncontrolled storming of local cytokines and chemokines. Typical symptoms include diarrhea, abdominal pain, and bloody stools. IBD imposes a global health and economic burden and significantly ruins the quality of life for patients. This pathologic consequences of autoimmune reactions under complex hereditary and environmental factors, are involved in multiple cytokines and chemokines severely and recurrently evoking innate and selective immunities. In IBD patients, the expression of pro-inflammatory cytokines such as interleukin (IL)-6, IL-12, IL-23, and tumor necrosis factor-α (TNF- α) is abnormally increased.
Improved cell-permeable nuclear import inhibitor (iCP-NI) has been developed by fusing hydrophobic cell-penetrating peptide (CPP), namely advanced macromolecule transduction domain (aMTD) with nuclear localization signal (NLS) of stress responsive transcription factors (NF-κB, STAT1/3, AP-1 & NFAT). iCP-NI suppresses the expression of major cytokines that cause IBD and restores colon tissue destruction (Figure 1). Ultimately, iCP-NI ameliorates IBD symptoms by regulating inflammatory cytokine signaling and recovering intestinal layer. For this reason, iCP-NI can be a very effective potential therapeutic agent for IBD.
Currently, we are developing oral formulations for iCP-NI to treat IBD patient-friendly beyond injections.
Figure 1. iCP-NI recovers the damage of mucosal and submucosal layers in the colon tissue of the Crohn's disease model.
PIPELINE | CV-15
iCP-NI, Autoimmune Uveitis
Superior Peptide-Based Biologics Against Severe Autoimmune Eye Disease That Can Lead To Blindness
Autoimmune Uveitis (AU) is an inflammatory eye disease that destroys eye tissue and causes layer swelling. AU is caused by excessive inflammation of the lens, retina, and optic nerve as well as a certain layer of the eye called 'uvea'. Symptoms of AU include blurred vision, dark, floating spots in the vision, and sensitivity to light. These diseases reduce vision and, if left untreated, can lead to vision loss. When non-infectious uveitis is induced, excessive cytokine expression occurs, and an abnormal immune response occurs. The response of Th1 and Th17 cells is essential for the onset of AU. In particular, the expression of cytokines such as IL-1, IL-17, interferon-γ (IFN-γ), and TNF-α is increased.
Therefore, local regulation of pro-inflammatory cytokine expression could be a suitable strategy for AU treatment.
iCP-NI capable of tissue-permeability can be a patient-friendly & powerful ophthalmic-immunotherapy by inhibiting the expression of various uveitis-related cytokines and inducing the normalization of destruction of eye tissue, as a more attractive agent with the development of eye drop formations (Figure 1).
Figure 1. iCP-NI (eye drop) restores the damage of the retinal layers in the model of uveitis, an autoimmune eye disease.
PIPELINE | CV-15
iCP-NI, Atopic Dermatitis
iCP-NI Cream Is A Powerful Therapeutic Against Inflammatory Skin Disorder
Skin layers play an important role to provide a physical barrier against physical dangers and function as an immunological organ that defend our body against various pathogens. However, dysregulation of the protective system of the skin can give rise to various types of inflammatory skin diseases, such as atopic dermatitis and psoriasis, which are common chronic inflammatory skin diseases that are mediated by immune cells, in particular, T cells.
Atopic Dermatitis is the most common inflammatory skin disorder that affects approximately 15-20% of children and 3-5% of adults worldwide in the developed and developing countries. The symptoms most often develop during childhood and is characterized by recurrent eczematous lesions (that is charactered by erythematous (red) skin with crusting, scaling, cracking and thickening patches) and intense itch and discomfort. Th2-type inflammation which is substantial for signaling via interleukin-4 (IL-4) and IL-13 is contributed to the pathogenesis of atopic dermatitis. The current treatment of atopic dermatitis is limited to the level of symptom relief due to complicated pathogenic causes.
The impact of atopic dermatitis produces a reduced quality of life and so far there is no treatment agent developed.
To deal with this medical need against atopic dermatitis, improved cell-permeable nuclear import inhibitor (iCP-NI) has been developed as an effective therapeutic agent by fusing hydrophobic cell-penetrating peptide (CPP) with nuclear localization signal (NLS) of NF-κB. iCP-NI is able to suppress the activation of pro-inflammatory pathways and secretion of pro-inflammatory cytokines in sepsis models. iCP-NI treated via cream formulation suppresses atopic dermatitis-related Th2 cell activation and recovers the expression of protein for skin barrier (Figure 1). The purpose of this project is to demonstrate the anti-inflammatory agent, iCP-NI will also solve chronic skin inflammatory diseases via patient-friendly formulation, cream or ointment.
Figure 1. iCP-NI (cream) restores the expression of filaggrin which is the main protein for skin barrier in the skin of atopic dermatitis model.
PIPELINE | CV-15
A Cream-Type Pro-Inflammatory Cytokine Blocker Against Relapsing Psoriasis.
Psoriasis is a common chronic inflammatory skin disorders, affecting about 2% of the worldwide population. Psoriatic lesions are histologically characterized by hyperproliferation, aberrant differentiation of keratinocytes and infiltration of immune cells into skin layers through activation of type 17 inflammation. From intensive studies of inflammatory skin diseases, cytokines produced by immune cells in the damaged skin affect the proliferation and activation of non-immune cells, which generates a complex inflammatory network, which, in turn, leads to chronic skin inflammation. The current treatment of psoriasis is limited to the level of symptom relief because there are many pathogenic causes.
To solve the problem of psoriasis, iCP-NI has been engineered to regulate nuclear import of transcription factors (NF-κB, NFAT, AP-1 and STAT) involved in activation of gene expression of key mediators of inflammation.
iCP-NI in cream suppresses psoriasis-related Th17 cell activation and the abnormal proliferation of keratinocytes in epidermis. (Figure 1). The main purpose of this study is to develop iCP-NI as anti-inflammatory reagent to solve autoimmune skin disorders via patient-friendly formulation, cream or ointment.
Figure 1. iCP-NI (cream) restores the damage of epidermal and dermal layers in the skin tissue of the psoriasis model.