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<li><a href="#About MusCure">About MusCure</a></li>
<li><a href="#Why MusCure">Why MusCure</a></li>
<li><a href="#Design">Design</a></li>
<li><a href="#Biosafety">Biosafety</a></li>
<li><a href="#Future Plan">Future Plan</a></li>
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<h2 id="Why MusCure">
<h2>Why MusCure</h2>
<p>During our brainstorming process, we realized the mighty potency of synthetic biology in medical treatments, especially in the therapy development of inflammatory bowel disease (IBD), one of the hardest-to-cure conditions in the world. Thanks to the well-understood genetics and its efficient heterologous protein expression capacity, Saccharomyces cerevisiae appears to be a promising chassis organism for developing biological therapies for IBD. Additionally, various synthetic biology components enable us to design multiple control systems, achieving precise and comprehensive control over the treatment. Viewing IBD treatments from a brand-new aspect, we found that biological therapy obtains tremendous advantages not found in traditional chemical drugs. As a result, we have chosen IBD therapy as our project focus of this year.</p>
<p>Comprising of Ulcerative Colitis (UC) and Crohn's Disease (CD), IBD is a chronic, incurable disease affecting people of all ages worldwide. According to the Global Burden of Disease (GBD), there was a notable increase of 175,904 individuals diagnosed with IBD from 1990 to 2021. Over 1 million residents in the USA and 2.5 million in Europe are estimated to have IBD, with substantial costs for health care. IBD patients normally suffer from abdominal pain and diarrhea, combined with intermittent fever and various extraintestinal symptoms such as arthritis. Besides, IBD is well-known for its complex and unclear pathogenesis, which also explains why no common and satisfying therapy exists.</p>
<p>In our research effort, we discovered that abnormal immune response triggered by the intestinal flora is strongly related to the disease. Meanwhile, recent studies have revealed that lactate possesses the capacity to limit CNS autoimmunity response, thus relieving the inflammation in the intestine. As for the method of administration, to avoid the possible side-effects cost by oral administration, we take the advantage of recently-discovered muscone receptor, hoping that inhalational administration can balance both efficacy and comfortability.</p>
<p>IBD is now one of the most common intestinal diseases in China. Because of the relatively low public awareness of IBD and lack of rigorous standard for diagnosing IBD, many patients are misdiagnosed in the early stage of the disease, wasting valuable treatment time. Thus, we also put in effort to raise the public awareness and educate the public about IBD and intestinal health through various means.</p>
<h2 id="About MusCure">
<h2>About MusCure</h2>
<p>In recognition of the limitations of current IBD therapy, we embarked on a journey to harness the power of synthetic biology in developing a biological therapy, which we named “MusCure” as the abbreviation of “Muscone to Cure”. Our primary objective was to engineer yeast capable of specifically colonizing at the inflammatory sites of the intestine and delivering lactate in response to the signals of muscone.</p>
<p>Based on the published paper and our patient interviews, oral administration has many drawbacks. For instance, parts of IBD patients have difficulty in swallowing the pills, and given the vulnerable intestine of the patients, oral administration can cause further nausea or vomiting. To address the shortcomings of oral administration, MusCure offers an “APE” solution: “Affordable, Potential and Efficiency IBD treatment”. The following sections will elucidate how our design accomplishes these goals.</p>
<h3>Current treatments</h3>
<p>Current treatments of IBD include surgical interventions, pharmacological therapies and nutritional therapies. However, these conventional IBD treatment methods still exhibit several limitations.</p>
<h4>Surgical Interventions</h4>
<p>Surgical interventions play an important role in the treatment of IBD, especially for patients who do not respond to medical therapy or who have complications. Surgical interventions are very effective, but because of the widespread use of ostomy techniques, they can have a significant negative impact on the patient's daily life as well as the injury.</p>
<h4>Pharmacological Therapies</h4>
<p>Pharmacological therapy is the core of IBD treatment, mainly including the following categories: aminosalicylic acid, glucocorticoids, immunosuppressants, biologics, antibiotics, probiotics, anticholinergics, etc. These drugs are usually immunosuppressive and increase the risk of infection with long-term use; Special targeted drugs have the disadvantage of being expensive.</p>
<h4>Nutritional Therapies</h4>
<p>Nutritional therapy plays an important role in the remission and prognosis of IBD. However, at present, nutritional therapy is faced with problems such as slow effect, long course of treatment, and insufficient targeting, which will affect the quality of life of patients.</p>
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<th class="border border-gray-300 p-2">Treatment options</th>
<th class="border border-gray-300 p-2">Cost</th>
<th class="border border-gray-300 p-2">Performance</th>
<th class="border border-gray-300 p-2">Indications</th>
<th class="border border-gray-300 p-2">Side effects</th>
<th class="border border-gray-300 p-2">Drawback</th>
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<td class="border border-gray-300 p-2">Surgery</td>
<td class="border border-gray-300 p-2">High</td>
<td class="border border-gray-300 p-2">Best</td>
<td class="border border-gray-300 p-2">Refractory to medical treatment, serious complications</td>
<td class="border border-gray-300 p-2">Surgical risks, postoperative infection, anastomotic leakage</td>
<td class="border border-gray-300 p-2">Invasive, may require long-term rehabilitation, and is irreversible</td>
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<td class="border border-gray-300 p-2">Drug</td>
<td class="border border-gray-300 p-2">Medium to high</td>
<td class="border border-gray-300 p-2">Good</td>
<td class="border border-gray-300 p-2">Mild, moderate, and severe, with no indication for surgery</td>
<td class="border border-gray-300 p-2">Infection, liver and kidney damage, drug allergy</td>
<td class="border border-gray-300 p-2">Long-term, severe side effects, individual differences in efficacy</td>
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<td class="border border-gray-300 p-2">Nutritional therapy</td>
<td class="border border-gray-300 p-2">Low to medium</td>
<td class="border border-gray-300 p-2">Average</td>
<td class="border border-gray-300 p-2">All, especially the malnourished</td>
<td class="border border-gray-300 p-2">Electrolyte imbalance, nutritional formula intolerance</td>
<td class="border border-gray-300 p-2">Poor effects, require professional nutritional guidance</td>
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<h2 id="Design">
<h2>Design</h2>
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<h3>Chassis organism</h3>
<p>Saccharomyces cerevisiae is a premier chassis organism for our project. As a kind of common yeast found in human gut, Saccharomyces cerevisiae is considered safe for human and has been extensively studied for its potential application in synthetic biology. As a eukaryotic organism, it possesses more complex and precise mechanisms for gene expression regulation, and various modification approaches also enhance its ability to secrete target proteins. Of note, it has been employed to prevent and treat various diarrheal disorders due to its capability to reshape the balance of gut flora. We believe that Saccharomyces cerevisiae is the best chassis organism to achieve our goal.</p>
<h3>Circuit</h3>
<p>In order to develop a biological therapy for IBD, two fundamental aspects are taken into our consider: controlled release of drug and targeting.</p>
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<h2 id="Biosafety">
<h2>Biosafety</h2>
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<p>As a biological treatment we are developing, its safety has always been at the top priority for us. To ensure our engineered yeast can't survive in the outside the gut, we introduced a suicide system using specific intestine marker, bile acid. In the intestine, bile acid binds to its receptor, which further activates the expression of Cl protein. Cl protein can inhibit the expression of suicide gene MazF. Once the yeast leaves intestine, lack of bile acid leads to successful expression of MazF, killing the engineered yeast. By introducing this system, we ensure that our yeast can only colonize and thrive in the intestine. Besides, nutritional-deficiency also provides a convenient and efficient approach for us to ensure biosafety. Our engineered yeast is uracil and histidine auxotrophic, further ensuring its safety.</p>
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<h2 id="Future Plan">
<h2>Future Plan</h2>
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<p>to be continue</p>
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