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import { InfoBox } from "../components/Boxes";
import { TabButtonRow } from "../components/Buttons";
import Collapsible from "../components/Collapsible";
import { SupScrollLink } from "../components/ScrollLink";
import { H2, H4} from "../components/Headings";
import { LoremMedium } from "../components/Loremipsum";
import { Circle } from "../components/Shapes";
import PieChart from "../components/Graph";
import PreCyse from "../components/precyse";
import { Section, Subesction } from "../components/sections";
import { symptomdata, SymptomDatensatz } from "../data/symptom-data";
import { drugdata, DrugDatensatz } from "../data/drug-data";
import { useTabNavigation } from "../utils/TabNavigation";
import PrimeEditingComplex from "../components/Complex-svg";
export function Description() {
const {goToPageAndScroll} = useNavigation();
return (
<div className="row mt-4">
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<p id="obenindescription" >We are proud to introduce our next-generation prime editing technology <PreCyse/> . We aim to develop an innovative gene therapy against cystic fibrosis, tackling the most common mutation F508del of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. We optimize lipid nanoparticles (LNPs) for the efficient and cell-specific delivery of our therapeutic mRNA. Current treatment strategies are limited in terms of speed, precision and effectiveness, often failing to achieve long-lasting improvements. In addition, high costs and limited accessibility of pharmaceuticals contribute to adverse prognosis of many patients. We want to develop a monthly applied which represents a cure that is more advanced and user-friendly compared to other medications due to its longer lasting time, lowering the frequency of use. </p>
<Section title="Our Motivation" id="Our Motivation">
<p>We chose to focus on CF and specifically the F508del mutation due to its prevalence and the severe impact it has on patients' lives. Additionally, our team includes members who have close friends affected by this condition, giving us a personal connection and a strong motivation to find a solution. By targeting the F508del mutation, we aim to develop a therapy that could potentially, not only benefit many CF patients and make a significant improvement in their lives, but also can serve as a template, which research groups can use to target other genetic diseases. </p>
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<img className="img" src="https://static.igem.wiki/teams/5247/placeholders/placehilderperson.jpeg"/>
</div>
Liliana Sanfilippo
committed
</div>
<Section title="Cystic Fibrosis" id="Cystic Fibrosis">
<Subesction title="Overview" id="Cystic Fibrosis1">
<div className="row align-items-center">
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<p data-aos="zoom-y-out" >Cystic fibrosis (CF) is the most common life-limiting genetic disorder in the Caucasian population. In Europe, CF affecting about 1 in 3,000 newborns
<SupScrollLink label="1"/>.</p>
<p> It is caused by mutations in the CFTR gene, which controls ions and water movement in cells. This leads to thick mucus, clogging airways, and frequent infections. The defective CFTR protein impacts the respiratory and digestive systems, causing chronic lung infections, breathing difficulties, and malnutrition. CF's severity varies, but it reduces life quality and expectancy. There are over 1,700 CFTR mutations; the F508del mutation is most common, present in 70% of cases. It prevents proper protein folding, affecting its function. </p>
<Collapsible id="fanzorcas-collapsible" title="Cas vs. Fanzor">
<p>The mutations can be divided into six classes <SupScrollLink label="9"/>:</p>
<p>Class I mutations prevent the synthesis of CFTR proteins altogether, meaning no channels are produced.</p>
<p>Class II mutations, which include the common F508del mutation (responsible for about 85% of cases <SupScrollLink label="10"/>), disrupt the maturation process of the protein. As a result, the defective channels are quickly degraded by the cell.</p>
<p>Class III mutations, known as “gating” mutations, reduce the likelihood that the CFTR channel will open correctly, impairing its function.</p>
<p>Class IV, V, and VI mutations are rare. These mutations result in the production of unstable or inefficient CFTR proteins, which do not function adequately and are produced in insufficient numbers.</p>
</Collapsible>
Liliana Sanfilippo
committed
<LoremMedium/>
</div>
<div className="row-if-small col-2 ">
<Circle text="1:3000 newborns worldwide"/>
<Circle text="x:y newborns in Germany"/>
<Circle text="kosten"/>
</div>
{/* <Linear
xAxis={[{ data: [1, 2, 3, 5, 8, 10] }]}
series={[
{
data: [2, 5.5, 2, 8.5, 1.5, 5],
},
]}
width={500}
height={300}
/> */}
</div>
<div className="col">
<img src="https://static.igem.wiki/teams/5247/charts-maps/cfper10-000.png"></img>
</Subesction>
<Subesction title="The CFTR Protein" id="Cystic Fibrosis2">
<figure>
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<img src="https://static.igem.wiki/teams/5247/placeholders/placehilderperson.jpeg"/>
</div>
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<img src="https://static.igem.wiki/teams/5247/placeholders/placehilderperson.jpeg"/>
</div>
</div>
<figcaption><b>Figure x.</b> </figcaption>
</figure>
Liliana Sanfilippo
committed
<p>Text about CFTR </p> <LoremMedium/>
<div className="figure-wrapper">
<figure>
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<img className="CFTR-gif" src="https://static.igem.wiki/teams/5247/fanzor/cftr-wt.gif"></img>
Liliana Sanfilippo
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</div>
<p>A multitude of mutations in the CFTR gene, exceeding 1,000, are responsible for the development of cystic
fibrosis. The most prevalent variant is F508del, observed in approximately 70% of affected individuals of
Caucasian descent in Canada, Northern Europe, and the United States<SupScrollLink label="14"/>. It is estimated that around 90% of
the European population and people of European heritage with cystic fibrosis carry at least one F508del
variant <SupScrollLink label="15"/><sup>,</sup><SupScrollLink label="16"/>. Analyses have demonstrated that the F508del mutation originated in Western Europe at least
5,000 years ago <SupScrollLink label="15"/>. </p>
<p>It is a deletion of the three nucleotides "CTT" at position 508, which removes the phenylalanine residue
without causing a frameshift. This deletion leads to defects in the kinetic and thermodynamic folding
of the NBD1 domain <SupScrollLink label="16"/>. However, this not only leads to misfolding of CFTR but also to defects in
trafficking and premature degradation, resulting in reduced surface expression of CFTR <SupScrollLink label="17"/>. </p>
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<img src="https://static.igem.wiki/teams/5247/charts-maps/cfper10-000.png"/>
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<QuizQuestion name="schreibweise" front="What do the codes F508del and F508del stand for?" back="they..."/>
</Subesction>
<Subesction title="Symptoms" id="Cystic Fibrosis4">
<p>Since the CFTR gene is expressed in nearly all tissues of the human body, cystic fibrosis affects as a metabolic disease a wide range of vital organs.</p>
<Collapsible id="symptoms-collapsible" title="How the symptoms affect different parts of the body" >
<TabButtonRow data={symptombuttonrowdata} opentype="meditabs" closing=""/>
<ButtonRowTabs data={symptombuttonrowdata} cla="meditabs"/>
</Collapsible>
</Subesction>
<Subesction title="Diagnosis" id="Cystic Fibrosis5">
Liliana Sanfilippo
committed
<p>About the ways one can be diagnosed </p> <LoremMedium/>
<div className="row align-items-center">
<div className="col" >
<img src="https://static.igem.wiki/teams/5247/placeholders/placehilderperson.jpeg"/>
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How newbornscreening affected the numbers.
<LoremMedium/>
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Liliana Sanfilippo
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</div>
<Subesction title="Treatment" id="Cystic Fibrosis6">
<p>Cystic fibrosis therapy means inevitably a complex and customized treatment plan for each patient. It consists of a range of components. These include medication such as CFTR modulators and antibiotics as well as inhalation therapy and mucolytics, physiotherapy, nutritional therapy and sports therapy. It is therefore essential that CF patients receive treatment at a specialist centre <SupScrollLink label="1"/>.</p>
<Collapsible id="drugs-collapsible" title="Different types of drugs" >
<TabButtonRow data={medibuttonrowdata} opentype="symptabs" closing=""/>
<ButtonRowTabs data={medibuttonrowdata} cla="symptabs"/>
<H2 text="CF treatment with gene therapy"></H2>
<p>While mentioned medications have improved the quality of life for numerous CF patients, they only manage symptoms rather than cure the disease. Moreover, most of them are expensive and not world-wide accessible. Our research is focused on the development of a gene therapy that targets the underlying cause of CF by correcting the defective CFTR gene. <PreCyse/> aims to halt disease progression and reduce the treatment burden for patients.</p>
<img src="https://static.igem.wiki/teams/5247/charts-maps/cfper10-000.png"/>
</Subesction>
</Section>
<Section title="Approach" id="Approach">
<p>To correct the mutation, we are utilizing Prime Editing technologies. Prime Editing is a genome editing technique that allows precise DNA modifications without causing double-strand breaks<SupScrollLink label="2"/>. Structurally, the Prime Editing complex consists of a Cas9 endonuclease fused to a reverse transcriptase (RT) and guided by a pegRNA, which directs the complex to the target site in the genome. </p>
<summary>Prime editing is a new method of gene editing based on an RNA-Protein complex. It was developed by a group of researchers revolving around Professor David Liu from Harvard University in 2019. <SupScrollLink label="9"/></summary>
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<div className="col">
<p>However, the Prime Editing complex is relatively large, posing challenges for therapeutic delivery<SupScrollLink label="3"/>. Additionally, Prime Editing has been shown to be relatively inefficient in terms of gene editing rates, which could limit its therapeutic utility<SupScrollLink label="4"/>. Our project aims to enhance the Prime Editing approach by miniaturizing its components. Fanzor, a recently discovered eukaryotic endonuclease, performs functions similar to Cas9, a crucial part of the Prime Editing complex, but is significantly smaller. We aim to substitute Cas9 with Fanzor. </p>
<p>Additionally, we plan to replace the reverse transcriptase in the Prime Editing complex with a smaller RT variant. Furthermore, MCP proteins will be added to the Prime Editing complex to increase its stability<SupScrollLink label="5"/>. </p>
</div>
<div className="img-right img-half col"><PrimeEditingComplex/></div>
<Collapsible id="fanzorcas-collapsible" title="Cas vs. Fanzor"> child </Collapsible>
<p>The pegRNA is optimized via an extension by a stem loop, which stabilizes the RNA by protecting it from RNases and serves as a binding site for the MCP, which also supports the secondary RNA structure.
This represents a major biosafety feature in that the complex is switched off after successful DNA editing and the subsequent increased influx of chloride ions into the cell. The pegRNA is combined with an optimized sgRNA resulting in higher on-target effect. Overall, its optimization leads to a longer shelf life and an increase in the biosafety of the complex. </p>
</Subesction>
<Subesction title="Delivery" id="Approach2">
<div className='row align-items-center'>
<div className='col'>
<img src="https://static.igem.wiki/teams/5247/delivery/sort-lnp-ohne-beschriftung.webp"/>
</div>
<div className='col'>
<p>We optimized LNPs as a robust delivery system to transport larger therapeutic cargo, such as Prime Editing mRNA, to lung epithelial cells via inhalation. LNPs were chosen over other delivery systems, like Adeno-associated viruses (AAVs), due to their superior cargo capacity and reduced immunogenicity. Our goal was to create a spray-dried lung-specific LNP named</p>
<img src="https://static.igem.wiki/teams/5247/delivery/airbuddy.webp" style={{maxHeight: "80pt"}}/>
<p>capable of efficiently delivering of our Prime Editing components, referred to as PrimeGuide, to lung tissues through inhalation. This approach is designed to advance precision medicine by ensuring targeted delivery with minimal off-target effects.</p>
<Collapsible id="Col1" open={false} title="LNPs explained">
<H4 text="LNPs and their impact on modern medicine" id="text" />
<p>LNPs are an advanced delivery system designed to transport therapeutic molecules like RNA, DNA or proteins into the cells. These nanoparticles are tiny spheres made of lipids that form a protective shell around the cargo. The size of LNs typically ranges from 50 to 200 nm in diameter, making them incredibly small - about 1,000 times thinner than a human hair [1]. </p>
<p>Overall, LNPs represent a significant advancement in drug delivery technology. LNPs offer exceptionally high drug-loading capacities, making them highly effective for delivering substantial amounts of therapeutic agents in a single dose. Their advanced design allows for the encapsulation of a large payload, which enhances the efficacy of treatments and reduces the frequency of administration [3]. By encapsulating and protecting therapeutic agents like mRNA, LNPs enhance the stability, targeted delivery, and effectiveness of treatments. Their ability to be tailored for specific delivery needs, such as targeting particular organs or overcoming physiological barriers, makes them a powerful tool in modern medicine [9].</p>
<H4 text="Protection of cargo" id="text" />
<p> The primary function of LNPs is to shield the therapeutic agents they carry, such as mRNA, from degradation and facilitate their delivery into cells. mRNA is a critical component in many modern vaccines and therapies, but it is highly susceptible to breaking down before it can reach its target within cells. LNPs address this challenge by encapsulating the mRNA, thus protecting it from harmful enzymes, like RNases and environmental conditions [2]. </p>
<H4 text="Delivery assurance" id="text" />
<p>LNPs come in various types tailored for different therapeutic needs. Solid Lipid Nanoparticles (SLNs) and Nanostructured Lipid Carriers (NLCs) enhance drug stability and solubility, while Liposomes, with their bilayer structure, are versatile for encapsulating both hydrophilic and hydrophobic drugs. Cationic LNPs are ideal for gene delivery due to their positive charge, whereas anionic and neutral LNPs offer reduced interaction and lower toxicity, respectively [3]. </p>
<p>To enhance their effectiveness, LNPs are designed with specific components. For instance, the Nebulized Lung Delivery 1 (NLD1) nanoparticle, a particular type of LNP, includes a combination of lipids and polymers that stabilize the mRNA and allow it to be delivered efficiently. This formulation includes small lipid particles that encapsulate the mRNA and can maintain stability for several days under proper storage conditions [2]. </p>
<H4 text="Size impact of pulmonary LNPs" id="text" />
In the context of pulmonary delivery, where the goal is to target the lungs, the size and properties of the LNPs are crucial. Particles smaller than 2 micrometers are particularly effective for reaching the alveolar regions of the lungs [11].
<H4 text="Role of surface modifications in targeting" id="text" />
<div className='row align-items-center'>
<div className='col'>
<figure>
<img src="https://ars.els-cdn.com/content/image/1-s2.0-S1773224724002156-gr3_lrg.jpg" alt="Aufnahme LNP" style={{maxHeight: "200pt"}}/>
Endosomal escape vs degradation of LNP cargo at endocytosis [4].
<div className='col'>
<p>LNPs are pivotal not only for shielding mRNA but also for ensuring its efficient delivery into target cells. They facilitate cellular uptake through endocytosis, where the cell membrane engulfs the nanoparticle. LNPs are acclaimed for their high drug-loading capacities, which greatly enhance their therapeutic effectiveness. However, the success of this delivery hinges on effective endosomal escape. Ideally, LNPs release their mRNA payload into the cytoplasm after escaping from endosomes. If this escape process is inefficient, the mRNA can be degraded by lysosomes, which poses a significant challenge for mRNA vaccines and therapies [4].</p>
</div>
</div>
<p>A crucial advancement in LNP technology involves the use of pH-sensitive cationizable lipids. These lipids remain neutral at physiological pH but become cationic in the acidic environment of endosomes. This shift in charge helps dissociate the nanoparticles and disrupt the endosomal membrane, enhancing the likelihood of successful endosomal escape [5]. </p>
<p>Moreover, the surface of LNPs can be customized to improve targeting. For instance, incorporating specific lipids or modifying the surface with charged groups can direct the delivery of mRNA to targeted organs like the lungs or spleen [6]. Additionally, LNPs can be engineered with targeting ligands or antibodies to precisely direct their payload to specific cell types, further enhancing their therapeutic efficacy [7]. Another approach can be chitosan-based nanoparticles have been explored for their ability to adhere to mucus and enhance drug delivery through the respiratory tract. These nanoparticles can penetrate through the mucus layer to reach the lung tissues more effectively [8]. This versatility in design is essential for optimizing the delivery and effectiveness of LNP-based therapies.</p>
</Collapsible>
<Collapsible id="Col2" open={false} title="Challenges of working with LNPs">
<p>Maintaining the stability of LNPs throughout formulation, storage, and delivery is critical, as factors like temperature changes, pH shifts, or mechanical stress can affect their integrity [1] [2]. Equally important is ensuring efficient encapsulation of the genetic material, as any inefficiency can lead to degradation of the therapeutic cargo or inadequate delivery to the target cells. Once inside the body, LNPs face the challenge of cellular uptake and successful endosomal escape [3] [4]. If they cannot escape the endosome after entering the cells, there is a risk that the genetic material will be degraded in the lysosomes, limiting the efficacy of the treatment. In addition, the formulation must minimize immunogenicity and toxicity, particularly with repeated dosing, which is often necessary for chronic diseases [2] [3]. Achieving this sensitive balance is crucial for maximizing the therapeutic potential of LNPs in gene delivery.</p>
<p>While these are general difficulties in the use of LNPs for gene therapy, further challenges arise when administering the LNPs via inhalation into the lungs, due to the unique environment and anatomy of the respiratory system.</p>
<H4 text="Challenges of inhalated lung-specific LNPs" id="chall2" />
<p>These challenges range from formulation and particle size to overcoming biological barriers and maintaining consistent dosing, all of which impact the overall efficacy of the therapy. </p>
<p>When transforming LNP formulations into inhalable particles, even greater attention must be paid to stability than is already the case. During processes like nebulization or spray-drying, LNPs are exposed to strong <strong>mechanical stress</strong> such as shear forces during aerosolization that can damage the LNP and thus their ability to protect and deliver genetic material effectively [5]. Ensuring that the LNPs maintain their structure throughout this transformation while remaining suitable for aerosol delivery is critical to the success of the therapy.</p>
<p>The <strong>size</strong> of the nanoparticles is another important factor. For successful lung delivery, LNPs should be smaller than 2 µm [6]. If the particles are too large, there is a risk that they will get stuck in the upper airways not able to reach the target cells; if they are too small, they may be exhaled before reaching the deeper lung tissue. The right particle size is crucial for the LNPs to reach the alveoli, where they can provide the greatest therapeutic impact.</p>
<p>Another major challenge is overcoming the lungs' natural <strong>protective barriers</strong>. The airways are lined with mucus and surfactants, which help to defend against pathogens, but also make it difficult for LNPs to be transported. In diseases such as cystic fibrosis, the thickened mucus presents an even greater obstacle, making it more difficult for the LNPs to reach the target cells [5]. The development of LNPs that can penetrate these barriers is essential for the success of gene therapy. </p>
<p>Finally, inhaled administration leads to fluctuations in the consistency of the <strong>dosage</strong>. Unlike intravenous administration, where dosing can be strictly controlled, the results of inhalation are influenced by factors such as the patient's breathing pattern, lung capacity and inhalation technique. These variables can affect how much of the LNP formulation actually reaches the lungs, complicating efforts to maintain a consistent therapeutic dose over time, which is a reasonable price to pay when you consider that inhalation is a non-invasive form of therapy compared to systemic therapy via injections into the bloodstream</p>
<p>All these challenges complicate the work with LNPs and present scientists with a great challenge, which makes working with LNPs even more important to find solutions.</p>
<p>To optimize AirBuddy for pulmonary delivery, we collaborated extensively with several experts, including <a onClick={() => goToPagesAndOpenTab('weber', '/human-practices')}>Prof. Weber, Dr. Große-Onnebrink</a> and <a onClick={() => goToPagesAndOpenTab('kolonkofirst', '/human-practices')}>Dr. Kolonko</a> as medical experts, <a onClick={() => goToPagesAndOpenTab('kristian', '/human-practices')}>Prof. Dr. Müller</a>, <a onClick={() => goToPagesAndOpenTab('radukic', '/human-practices')}>Dr. Radukic</a>, <a onClick={() => goToPagesAndOpenTab('moorlach', '/human-practices')}>Benjamin Moorlach</a> and the <a onClick={() => goToPagesAndOpenTab('biophysik', '/human-practices')}>Physical and Biophysical Chemistry working group</a> as academic experts form Bielefeld University and FH Bielefeld as well as <a onClick={() => goToPagesAndOpenTab('corden', '/human-practices')}>Corden Pharma</a> and <a onClick={() => goToPagesAndOpenTab('rnhale', '/human-practices')}>RNhale</a> as industrial experts. Throughout the <a onClick={() => goToPagesAndOpenTab('delivery head', '/engineering')}>development process</a>, we tested two commercially available kits: the <strong>Cayman Chemical LNP Exploration Kit (LNP-102)</strong> and the <strong>Corden Pharma LNP Starter Kit #2</strong>. While the Cayman kit demonstrated limited transfection efficiency, the Corden Pharma formulation significantly enhanced cellular uptake in lung tissues. Building on this, we integrated the <strong>SORT LNP</strong> method based on Wang's research [1], making our nanoparticles lung-specific. Additionally, we employed the <strong>spray-drying technique</strong> in cooperation with RNhale [2] to improve the stability of our LNP, ensuring that it withstands the inhalation process without degradation. This stability is crucial for the efficient delivery of mRNA into lung epithelial cells, where PrimeGuide can effectively perform genome editing.</p>
<img src="https://static.igem.wiki/teams/5247/delivery/big-plan-inhalation-teil-del.webp"/>
</div>
<p>To evaluate the <strong>delivery efficiency</strong>, we transfected HEK293 and CFBE41o- cells using fluorescent cargo and quantified the results through FACS analysis. We also ensured that AirBuddy meets the necessary standards for safety and efficacy since we conducted extensive <a onClick={() => goToPageAndScroll ('In-Depth Characterization of LNPsH', '/materials-methods')}> characterization of the LNPs </a>using techniques such as Zeta potential analysis, Dynamic Light Scattering (DLS), Scanning Electron Microscopy (SEM), and Cryogenic Electron Microscopy (cryo-EM). These methods confirmed the uniformity, stability, and optimal size distribution of the nanoparticles. Furthermore, <strong>cytotoxicity assessments</strong> including MTT and proliferation assays demonstrated that our LNPs are biocompatible and do not impede cell growth or function by the incorporation of <a onClick={() => goToPagesAndOpenTab('it4', '/engineering')}>PEG</a> and other ambivalent components. These findings reinforce AirBuddy's potential as a safe and effective tool for pulmonary delivery, with broad implications for gene therapies targeting lung diseases.</p>
</Section>
<Section title="Our Vision" id="Our Vision">
<p>We are envisioning a potential integration into a broader therapeutic framework involving customized gene editing tools for various genetic disorders, that present similar difficulties to the F508del mutation, as well as other genetic diseases of different causes. This could include collaborations with pharmaceutical companies to develop new treatment modalities for genetic diseases beyond cystic fibrosis, utilizing advanced delivery systems and personalized medicine approaches. </p>
<H2 text="Editing Statistics"/>
<PieChart /> {/* Render the PieChart component */}
</Section>
<Section title="References" id="References">
<ol>
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</Section>
node: createDrugSteckbrief(drugdata[0]),
buttonname: "Antibiotics",
cssname: "Antibiotics"
},
{
node: createDrugSteckbrief(drugdata[3]),
buttonname: "Enzymes",
cssname: "Enzymes"
cssname: "Symp-First",
main: true
},
{
buttonname: "Intestines",
cssname: "intestines"
},
{
node: createSymptomSteckbrief(symptomdata[2]),
buttonname: "Liver",
cssname: "liver"
},
{
node: createSymptomSteckbrief(symptomdata[3]),
buttonname: "Sexual glands",
cssname: "Sexual glands"
},
{
node: createSymptomSteckbrief(symptomdata[4]),
buttonname: "Lungs",
cssname: "lungs"
},
{
node: createSymptomSteckbrief(symptomdata[5]),
buttonname: "Skeletal System",
cssname: "Skeletal System"
},
{
node: createSymptomSteckbrief(symptomdata[6]),
buttonname: "Skin",
cssname: "skin"
},
{
node: createSymptomSteckbrief(symptomdata[7]),
buttonname: "Nasal mucosa",
cssname: "Nasal mucosa"
node: createSymptomSteckbrief(symptomdata[8]),
buttonname: "Brain",
cssname: "brain"
]
function createSymptomSteckbrief(data: SymptomDatensatz){
for (let index = 0; index < data.introduction.length; index++) {
examplelist.push(
<div className="row">
<div className="col-2">
<div className="symptom-img-wrapper">
<img src={data.picture} className="symptom-img"/>
</div>
</div>
<div className="col">
</div>
)
}
function createDrugSteckbrief(data: DrugDatensatz){
for (let index = 0; index < data.examples.length; index++) {
for (let i = 0; i < data.examples[index].text.length; i++) {
absaetze.push(
<div key={index+500} className="drug">
<div className="row">
<div className="col-2">
<div className="symptom-img-wrapper">
<img src={data.picture} className="symptom-img"/>
</div>
</div>
<div className="col">
{data.introduction}