Diagnosing Cystic Fibrosis by Theratyping with CFTR Modulators

Temperature rises, feeling tired 24/7, and suddenly you’re drinking that warm soup that isn’t much of help.

We know the drill. You’re sick.

For as long as I can remember, I’ve only been sick like 5 times, and I’m not all that familiar with the feeling, but from what I’ve seen, it doesn’t look amusing at all.

We’ve had illness and diseases since the beginning of time, and has affected so many lives. As obvious as it may seem, the main cause of death is diseases, and the one thing that every single person relies on during these difficult time, is medicine. Throughout the years, our knowledge on medications and drug response has expanded. It’s obvious, that everyone has distinctive biological aspects, so we do we all use the treatments? Why do we all just expect medicine to have the same effect on all of us, when we’re all different (scientifically)?

Since the time I was born, medicine has never really had THAT big of an affect on me. To be honest, the only reason I ever had it, was because of the grape flavour. And if medicine didn’t work, little 7 year old me would just devour a bucket of ice cream. The expected result is a person becoming even more sick, but I would end up completely normal.

A sneeze and a cough is bearable but for a person who has a disease, it can seem a bit terrifying. One of the most modern approaches to an illness, is through personalized medicine, and surprisingly, its the best shot for healthcare. A genetic disease, known as cystic fibrosis, is being treated with personalized medicine at the moment. But curing a diseases isn’t just as simple. Many factors need to be considered in order to have the best outcome.

Behind the scenes of Cystic Fibrosis

One of the global highlights throughout history, has been the discovery of the microscopic perceptions of the body (you know, the process of cells, organs, and all that molecular-sized materials). The more discoveries made about the body and disease, the more effective treatments were developed. A diseases that is being treated at the moment by individualized medicine, is cystic fibrosis or CF.

Cystic fibrosis isn’t just an ordinary disease, but it’s one of the main causes of life-shortening deaths. CF patients are diagnosed at a very early age, and usually die near their 30s. This disease has been around for almost a hundred years, and between those years, many efforts and movements have taken place to solve the problem. But we still have deaths winning over cure.

The science behind cystic fibrosis is basically about mutations in a gene that cause damages to other things. CF affects different organs, like the pancreas, liver, intestine: but mainly the lungs. And from what we know, the lungs is definitely a more complex pipe-like structure. It’s a bunch of interconnected pipes, that transact several gases, such as oxygen, carbon dioxide.

As air passes through these tunnels, it’s cleaned through a substance called mucus. With a texture of putty, it captures all non-essential products found in the air inhaled, as a result: purifying the oxygen. Dust and germs get stuck within the mucus, and using the help of cilia (an organelle in a string-like structure), it moves the mucus filled with germs/dust out of the airway, and a new layer is formed.

A person with cystic fibrosis experiences a scenario. A CF patients’ lungs consist of thick heavy mucus, that the cilia is unable to move. As a result, the mucus is stored in the airways, and can be develop infections, or a bacteria.

But why does mucus in CF hold this texture?

Not just the lungs, but most of the organs in our body is very dependant on secretions. Secretions in the lungs play as an important factor to creating mucus. In the lungs, secretions occur within the respiratory ciliated epitheliums.

This certain secretions involves 3 main elements: Sodium, chloride, and water.

Chloride is transported in and out of a cell, through a CFTR Protein (a chloride channel), meanwhile other specific elements are transported through a designated channel.

To have an effective protein, the structure should be accurate. CF patients have proteins that are abnormally structured due to the lack of 3 genes that instruct phenylalanine (an amino acid that makes CFTR proteins) In cystic fibrosis, the protein is dysfunctional, and can cause unusual transportations of chloride.

During these transportations, chloride attracts water, and this water helps build up over 95% of the mucus. In CF, a patient usually has a malfunctions in the CFTR protein which affects other channels. The transportation of sodium, chloride and water is disrupted. In most cases, chloride is trapped in the cell, and without water attractions the mucus becomes dry.

Mutation (F508del) → Deleted genetic code: phenylalanine → Abnormal protein structure → Dysfunctional Chloride transportation → Lack of water attracted for the mucus

To learn more about Cystic Fibrosis (CF) — “What 90% of people don’t know about Cystic Fibrosis”

Throughout the years, many therapies for cystic fibrosis have been developed, yet the solutions are inaccurate, and ineffective. The life expectancy for a CF patient is limited, therefore steps or initiatives taken to develop a cure for the disease in urgency. It’s as if, we have a thousand keys, and we need to identify that one key, that unlocks the door. Unfortunately, we just haven’t found it.

Whenever there isn’t a cure or solution to a disease, we take the “guaranteed root”, also known as therapies.

A certain type of therapy used for cystic fibrosis — are modulators.

Modulators

Definition: Modulators are substances that bind to the receptors of a cell, and change the reaction of a receptor to stimulus

Modulators can be imagined as the ‘superhero’ to the problem. They can solve irregular experiences in a cell, usually by changing the receptors 3D structure. This occurs, since modulators bind to regulatory sites instead of the active site on the protein, resulting in major changes. They are able to alter the affinity, productions, or efficacy of other substances acting on a receptor.

Affinity: Ability to bind to a receptor

Efficacy: Ability to activate a receptor (If the efficacy of a substance is 0, then its called an antagonist)

The location in which the endogenous agonists bind to, is called the “orthosteric site”. However, modulators don’t bind to this site, but instead allosteric sites.

Example:

A modulator (Allosteric modulator) at work!

Components of the image:

A = Orthosteric agonist

B = Orthosteric site

C = Allosteric modulator

D = Allosteric site

E = Receptor

F = Receptor’s response

Description of the image:

  1. The Orthosteric agonist binds to the orthosteric site of a receptor (A and B bind)
  2. Allosteric modulator binds to allosteric site (C and D bind)
  3. Modulator affects the affinity and efficacy of an agonist (The binding of C/D affects A/B)
  4. Modulator may also act as an agonist and yield an agonistic effect (3)
  5. Modulated orthosteric agonist affects the receptor (4)
  6. The receptor response

The site that an modulators would bind to is different from a site an endogenous agonist* would bind to. However, modulators and agonists can both be called “receptors ligands”. Ligands are the components that interact with proteins in target cells, that are affected by chemical signals.

Endogenous agonist: a certain receptor that is naturally produced by the body (binds + activates that receptor). For example: The primary endogenous agonist for dopamine receptors is dopamine.

There are different types of modulators — positive, negative, and neutral.

Modulators types:

Positive Modulators: Increase response of a receptor (by increasing probability of an agonist binding with a receptor. Therefore, increasing the ability to activate the receptor)

Negative Modulators: decrease the agonist affinity

Neutral Modulators: Has the ability to prevent modulators from binding to an allosteric site. (Doesn’t always affect agonist activity).

For cystic fibrosis, researchers use a particular type of modulator known as CFTR Modulators. These CFTR Modulators target mainly the CFTR protein, and develop different solutions to solve abnormal transportation of chloride ions.

CFTR Modulators

Similar to the allosteric modulators, CFTR modulators were developed to correct malfunctioning proteins caused by the CFTR gene. There are a variety of mutations in a gene that result in a change to CFTR proteins, thereby there are multiple modulators to adapt to each type of mutation. There are 4 main different categories of modulators:

Types of CFTR Modulators

1. Potentiators

Overall, a potentiator is a reagent that enhances sensitization of an antigen. Potentiators are used in process that require enhancement of agglutination to detect antibodies or antigens in a patient’s blood sample. They are also known as “enhancement reagents”.

Reagent: a substance or compound added to a system to cause chemcial reaction

Antigen: An antigen is any substance that causes your immune system to produce antibodies against it.

In Cystic Fibrosis, the CFTR proteins are used as a channel, in a tunnel shaped structure that is allows chloride particles in and out of a cell, by a gate. In some cases, the CFTR protein can resists the flow of chlorides. During these problems, potentiators (CFTR Modulators) are inserted to hold the gate open.

Poteniators = gatekeepers

2. Correctors

A wise man once said, “Nothing is perfect”. But when it comes to biology, having ‘perfect’ measurements, and structures is essential. It’s not like a tiny mistake can just pass through, instead a small change in gene, can form a dysfunctional protein, and lead to a disease. The role of a corrector os to fix the shape of the protein, and form the right 3D shape.

One of the most common mutations shown in CF, is F508del — this mutation specifically produces a deformed CFTR protein structure. Therefore, correctors help to reform the shape of the protein, and traffic back to the cell membrane.

3. Amplifiers

One last type of CFTR modulator is the amplifiers. Amplifiers increase the amount of CFTR Protein that the cell makes. A certain type of mutation in the gene, results in the consistent and excess amount of dysfunctional CFTR Protein production. Amplifiers are used to significantly increase the number of CFTR channels, and lead to a higher chance in the body naturally developing a functional channel.

Examples of CFTR Modulators

(WARNING: there may be confusing words ahead, but they are 100% real!)

There are currently 4 types of CFTR Modulators that are used as therapies for people that have cystic fibrosis.

Kalydeco (ivacaftor)

Kalydeco is a drug used for gating mutations. For cystic fibrosis, the ‘gate’ modulator is known as potentiators (kalydeco is an example of a potentiator). This particular modulator, binds to the defective protein at the cell surface and opens the chloride channel, holding the gate open. As a result, it allows chloride to flow through and regulates the amount of fluid on the surface of the cell. This treatment is meant for people aged 4 months and older, and have 97 mutations.

Orkambi (lumacaftor/ivacaftor)

Orkambi is a therapy composed of a combincation of lumacaftor and ivacaftor. Lumacaftor is a modulator known as a corrector. It contributes on protein reformation, and relocates its to the surface of the cell. Unfortunetly, lumacaftors aren’t as effective, since it only allows 1/3 of the CFTR protein to reach to the cell surface, and it transports only a limited amount of chloride. This treatment is specifically meant for ages 2 and older, that have 2 copies of F508del mutations.

Symdeko (tezacaftor/ivacaftor)

Symdeko is a tezacaftor and ivacaftor. Tezacaftor, a type of corrector, is very fimiliar to lumcaftor in Orkambi: forming the sturcture of a CFTR protein, traffic to the cell surface, and puts it in a fixed position in the cell memebrane. The difference between these two correctors (Orkambi and symdeko) is that symdeko has been shown to have fewer side effects. This treatment is specified for ages 6 and older with 2 copies of F508del mutations.

Trikafta (elexacaftor/tezacaftor/ivacaftor)

Trikafta is known to be one of the newest and most advanced modulators. This is next-generation correcotor (elexacaftor), which is combined with tezacaftor and ivacaftor.

The elexacaftor in the modulator helps to reform F508del-CFTR proteins. Meanwhile, tezacaftor and ivacaftor, helps the CFTR protein in performance.

This treatment is for CF patients aged 12 and older, who have at least one copy of the F508del mutation.

With the help of technology, there have been many scientific breakthroughs, and helped advance our understanding of genetics, and how its one of the root causes of diseases. Based on a CF patients genetic sequence, and other biological data, scientists and researchers have developed modulators.

Modulators play a huge role in precision medicine, since particular drugs are supplied based on genetic information. Based on a certain type of mutation in the gene, a specific modulator is given. Research shows that over 90% of people that have CF, are in a huge advantage of CFTR modulators.

Organizations are developing “theratyping’ which matches treatments to a certain type of mutation, and unlocking the maximum amount of benefits that a person could receive from a modulator.

“The goal of theratyping is to identify which mutations respond to certain CFTR modulators, therefore helping people with rare CFTR mutations gain access to already approved CFTR modulators quickly and safely.” — Cystic Fibrosis Foundation

Building medications for diseases, takes almost a decade. Along the way, there needs to be a high level of accuracy, and needs to be FDA approved. In most cases, the treatments that are established, aren’t personalized at all. The whole point of theratyping is to get find the ‘right key’ faster. Personalized medicine isn’t just about precise outcomes, but also provided the right services, at the right time, to the right person.

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Sanvi Rao

Sanvi Rao

Hey! I’m Sanvi. A 14 year old, who loves a challenge and is super passionate about learning the world’s biggest problems.