Team:SCU-WestChina/Implementation
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Implementation
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Part I Anti-fibrosis drugs——lung knight
Market demand
Idiopathic pulmonary fibrosis is a chronic, progressive, fibrotic, and interstitial lung disease of unknown etiology. It can cause pulmonary fibrosis, form permanent scar, and lead to irreversible and continuous decline of pulmonary function. In recent years, the incidence of IPF in China has been increasing gradually, with high mortality and short survival time.
According to statistics, there are more than 300 million idiopathic pulmonary fibrosis patients in China at a cost of nearly $2 billion. 80% of patients die within 5 years after diagnosis, and the absence of lung transplantation can lead to a 100% mortality rate. Therefore, idiopathic pulmonary fibrosis is also known as "non-cancerous cancer". There is no clear cause of IPF. Smoking, dust and infection are all risk factors for IPF.
However, under the huge demand for treatment, drugs that are targeted to the disease show obvious shortcomings. both nidanibu and pirfenidone, commonly used in IPF in The Chinese market, are faced with such adverse factors as high price, poor curative effect, lack of complete treatment, high drug dependence, and severe toxic and side effects. Therefore, it is of great significance to create and invent a highly targeted drug to overcome the shortcomings of existing treatment schemes, precisely target pulmonary fibrosis tissue, and reverse the fibrosis process.
Proposed target users
In order to provide a drug with more clinical value and higher patient satisfaction, we interviewed patients and doctors to investigate the needs and expectationsof these people directly related to the product (HP) . From their answers, we further understand that the therapeutic effects of the current drugs are not ideal. The side effects are huge but the price is very expensive. Many patients are very disappointed with the existing drug treatments. The doctor interviewed told us the biggest challenge in treating the disease is that we currently have no solution for end-stage pulmonary fibrosis, and the fibrosis cannot be reversed.
In response to the feedback from patients and doctors and the shortcomings of existing drugs that we knew through research, we hope to design a drug that has the characteristics of small side effects, strong targeting, low cost and easy to take. This drug can not only prevent the disease process of fibrosis and even reverse the process of pulmonary fibrosis to a certain extent.
Drug design, delivery and use
Our drug design consists of two parts.
In Design I , we designed the TGF-β truncated receptor. In order to inhibit TGF-β, which plays a key role as an initiating trigger in the entire irreversible fibrosis process of IPF and thus prevents the entire lung fiber process, we designed a series of TGF-β truncated receptors. The TGF-β truncated receptor retains only the TGF-β binding domain of the receptor but removes the signal transduction-related domains. Then we used z-Dock to fit its parameters and selected truncated body No. 4 as the component of this pulmonary fibrosis drug。
In Design I, we designed to postpone the progression of IPF and stabilize the condition by targeting and binding TGF-β. In Design II, we hoped to use plasmin to degrade collagen deposits, and therefore reversing the fibrosis process. By linking the type I collagen targeting peptide SILY with lysine analogues such as tranexamic acid, the type I collagen is labeled with molecular markers, so that type I collagen is filled with flags like an old general on the stage and can recruit plasmin on the fiber interface.
By combining design I and design II, we can postpone the disease progression as well as reverse the fibrosis process.
For the delivery and use of drugs, we have also made targeted designs for the needs of IPF patients. We chose liposomes to encapsulate the drug to ensure the tenderness and safety of the drug, while reducing its toxicity and side effects. After completing the drug package, we will atomize the drug to facilitate dose control, maximize patient use and reduce the discomfort and pain of patients when taking drugs.
Experimental verification and product advantages
Specifically, the advantages of this product are as follows:
① This product can directly block the upstream pathogenic signal factors of IPF and significantly slow down the process of pulmonary fibrosis.
②The product targeting segment is like navigation, which can accurately target the lesion and reduce the toxic side effects of drugs.
③We use liposome-embedded drug delivery system to efficiently deliver drugs to the affected area through the lungs to achieve gentle drug delivery.
④The medicine is packaged in sticks, which is convenient for patients to use.
And function verification would be carried out in three degree:
(1) Traditional Animal Degree:
We would carry out our animal studies in Prof.Hua Jingwan’ lab, where the techinicians and students are expert in PF animal model evaluation.
For one thing, we would test proteins’ function with serum factors level, tissue slice level as well as animals healthy level.
For another, we will also do deeper pharmacokinetic study to make sure that our drugs are metabolized properly and efficiently.
(2) Organoid Aeration Test
As lung is not that easy to observe its motion directly, we are planning to expand our research to test the drugs functiton with organoid microchips, and Prof. Xie Huiqi generously provide us with an excellent material (PU-SIS), which owns good biocompatibility and good elasticity) to do the next work.
(3) Clinical Trials in WestChina
After getting permission from professors who experts in Pneumology Department in WestChina Hospital, a series of clinical trials will be conducted at WestChina Hospital to verify the safety and efficacy of our drugs.
Future outlook
After the safety and effectiveness of this product have been confirmed by animal experiments, we will gradually carry out clinical trials with the support of West China Hospital of Sichuan University and relevant doctors and professors. Clinical trials will test whether our drugs have truly excellent clinical value and patient satisfaction.
Part II The Drug Screening Platform
Demand
With the widespread acceptance of precision medicine, an increasing drug researches have focused on the targeting ability of drugs to reduce their side effects. Different from the rapid development of chemical small molecule drugs in the last century, today more and more protein drugs are entering clinical trials and the drug market. The protein drug usually features low side effects and high biocompatibility, which is a type of drugs with high application value. Scientific researchers are paying high attention to this field.
Based precision medicine, we have built a screening platform for targeted recombinant protein drugs, which is especially suitable for drug screening for fibrotic diseases. Our platform is in line with the current drug development. Through the platform construction, we hope to improve the efficiency of drug development.
Target Users
Our drug screening platform is based on the concept of precision medicine, which aim at minimize the side effect of drugs. It includes the selection and verification methods of targeting probes, the design and optimization strategy for protein sequences. It is worth noting that we are innovatively constructing a lung organoid model based on the PU-SIS material, which is a verification platform for pulmonary fibrosis drugs, which makes up for the lack of credible animal models of idiopathic pulmonary fibrosis.
The drug screening platform is especially suitable for fibrotic diseases, and provides a design and verification idea for the majority of recombinant protein drug developers. We expect that the platform can be used by more scientific researchers and get feedback.
The way to use our platform
The design and verification of protein drugs based on our platform is divided into three stages, namely sequence selection stage, expression stage, and verification stage. The required technologies are cell-free protein synthesis, protein expression in E.coli, SPR, organoid construction, and drug metabolism assay using Gastroplus.
Challenge
- The reliability of our platform still needs more verification, especially through clinical trials.
- The construction of organoids is still being explored and optimized.
- The expression and purification system of recombinant protein still needs continuous improvement, which requires a lot of experience.
