Cystic fibrosis is a disease which occurs at a rate of 1 in 600,000 people in Japan. When it comes to Cystic fibrosis, viscous secretions are excessively secreted to major organs throughout the body such as the lungs and pancreas, resulting in dyspnea, digestive disorders in patients. At this stage there is no drug effective for radical treatment, and it has been classified as a designated intractable disease in Japan. Ms. Wenqian Yang tackled this difficult issue with the belief “Even rare diseases are worth researching as long as the patient is there”.
The human body is comprised of over 60 trillion cells which are controlled by genes: subunits of DNA located in the cell nucleus that code for all of the information and programming of a cell. The DNA carries the genetic blueprint used to make all of the proteins that the cell requires. Every gene contains a particular set of instructions which codes for a specific protein. If the sequence of DNA is altered, abnormal proteins are produced. Gene therapy utilizes nucleic acids such as DNA or RNA as drugs to treat diseases by genes disruption, insertion or correction in order to modulate diseases caused by incorrect gene sequences. This strategy allows for treatment of diseases that cannot be treated with conventional small molecule drugs or biologics, such as protein or antibody therapy.
Gene therapies using genes, aptamers, and antisense oligonucleotides have been showing promising results in the laboratory. However, full translation of such therapies into the clinic requires a formulation that can achieve efficient gene modification with high safety and minimal side effects. Unfortunately, nucleic acids are both highly inefficient and extremely immunogenic when administered alone, which significantly limits therapeutic applications. The human body has evolved to be highly resistant to gene modification, as this is the primary method of viral replication. Thus, direct injection of genetic material into the blood stream has nearly no effect, as the genes will be rapidly destroyed by nucleases or circulating immune cells. Moreover, due to the small size of the nucleic acids, they are easily excreted as urine from the kidneys, which in turn means that nucleic acid medicines must be delivered to the cells directly to evade kidney excretion. Therefore, the nanomedicine was developed; by covering the nucleic acid drug with a polymer, the size of the drug is increased, so the nucleic acid drug can be carried close to the target cells without being excreted as urine from the kidney.
Although our current polymeric nanocarriers have enhanced gene delivery properties, after nanomedicines were administered in vivo, there are many macromolecules present in the body which may destroy nanomedicine, they may be broken. Furthermore, when the unbroken nanomedicines reach near the target cell, it can easily be taken up by an acidic container endosome before playing its role and can be digested by a lysosome. Thus, to overcome the bottlenecks of nucleic acid therapies, nanomedicines should be designed to evade recognition as a foreign body by living organisms, and also avoid being digested by an endosome and a lysosome.
To overcome the bottlenecks of nucleic acid therapies, we are currently introducing functional amino acids into our polymeric nanocarrier to enhance function and stability, including the ability to escape cellular destruction in the endosome, as well as reversibly crosslinking the nanocarrier to enhance stability in circulation while allowing for a stimuli responsive release of the gene into the cell. As amino acids are the building blocks of proteins, the addition of amino acids into our nanocarrier is not expected to have any increase in toxicity or adverse effects. As there are 100 amino acids to choose from, some amino acids have stronger interaction with nucleic acids and some of them have better endosome escape stability, so molecular dynamic simulations are being carried out to provide an exhaustive exploration at the atomic level.
We would like to apply our gene therapy to treat the genetic disease cystic fibrosis (CF). Cystic fibrosis is a genetic disease which occurs in roughly 1 in 600,000 Japanese citizens. There are no effective drugs for treatment of CF, and it is classified as a rare disease by the Ministry of Health, Labor, and Welfare of Japan. As the exact cause of CF is known to be a mutation of the CFTR gene, we believe that genetic therapy to suppress the expression of the mutant gene can be an effective treatment that could enhance the quality of life for all CF patients. Our novel polymeric nanocarrier for genetic material is a promising design strategy for treating CF, and we hope that you can join us in our goal to treat CF.
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|June 2019||Challenge to crowdfunding|
|August 2019||Start experiment|
|December 2019||Patent application|
|March 2020||Article writing|
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