More Ontarians will be flagged for iron deficiency after doctors advocate for change to guidelines
What Is Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)?
The cystic fibrosis transmembrane conductance regulator (CFTR) is a complex protein that helps maintain fluid balance in several organs. Mutations in the CFTR protein can lead to symptoms of cystic fibrosis (CF).
The CFTR is a type of complex protein molecule. Proteins are molecules made up of amino acids. Each cell in the body contains proteins.
Proteins play several important roles. They help build and repair body cells, control many bodily functions, and help transport nutrients around the body.
The CFTR protein helps balance water and salt in many of the organs.
CF is a genetic condition in which mucus builds up in the lungs and digestive system. People with CF have changes to their CFTR protein that affect how it works. This can affect the body in several ways.
The CFTR protein functions as a channel across the membrane of certain body cells. The membrane is the barrier that surrounds every cell, protecting and organizing them.
It helps maintain the balance of water and salt on many surfaces in the body, such as:
The CFTR protein helps regulate how the body absorbs and produces salts and fluids in these areas as part of cells that produce:
People have a gene that tells their bodies how to make the CFTR protein. If a person has CF, they have mutations to this gene.
Their bodies then make faulty or do not produce enough CFTR proteins. This affects the movement of salt and water in and out of their cells. This leads to thicker and stickier mucus, which can produce symptoms that affect many of the organs.
Cystic fibrosis most often affects the lungs. The CFTR proteins affect how water and chloride move in and out of cells in the lungs, leading to:
Chloride is part of salt. Less water outside the cells causes mucus in the airways to dehydrate and thicken, leading to mucus sticking in the airways. This causes:
The pancreas is a small organ that helps break down parts of food during digestion using fluids called enzymes.
These enzymes flow from the pancreas in small tubes. In people with CF, the CFTR protein causes mucus in these tubes to thicken, blocking the tubes.
This causes enzymes to build up in their pancreas instead of reaching their digestive system. This can lead to several complications, such as pancreatic insufficiency, which is where the small intestine cannot properly digest food.
The CFTR can affect various other organs and systems in people with CF.
Immune system
Thicker mucus in the lungs may build up and further trap bacteria. This may lead to more inflammation and make it harder for the immune system to fight infections.
Bones
CF may cause issues with digestion due to the effect of CFTR on the pancreas. This may include malnutrition, which can lead to the body not getting the necessary vitamins and minerals.
Malnutrition may also lead to a lack of vitamin D and calcium, which are essential for healthy bones. People with CF may have brittle or weak bones, which can lead to fractures.
Liver, bile ducts, and gallbladder
People with CF may have sticky or thicker bile in the bile system. This can cause irritation and inflammation in the bile ducts. This irritation may lead to:
Sweat glands
The effect of CFTR on the movement of sweat and water in the body may cause very salty sweat or salty skin.
Reproductive system A note about sex and gender
Sex and gender exist on spectrums. This article will use the terms "male," "female," or both to refer to sex assigned at birth. Click here to learn more.
Most females with CF are fertile and can become pregnant, but some may take longer to conceive. They may also have:
Several treatments for CF can help manage symptoms or complications.
CFTR modulators are medications that improve how the CFTR protein works. They also help multiple organs in people with CF, as well as:
Healthcare professionals use genetic testing to check for mutations to the CFTR gene. Genetic testing can determine whether someone has CF or is a carrier for the CFTR gene mutation.
The tests can use a sample from a person's blood, saliva, or cells rubbed from inside their cheek.
The CFTR is a protein that regulates the composition of mucus and affects the movement of fluids within the cells of the body.
People with CF have CFTR proteins that do not work correctly. This can lead to thicker mucus around the body. They may then experience several symptoms that affect their lungs, digestive system, and other organs.
Certain medications for CF can help manage symptoms and prevent complications associated with CFTR.
The Future Of Rare Disease Treatment With Precision Medicine
Understanding rare diseasesPrecision medicine and rare diseasesGenetic and molecular profilingTailoring treatments for rare diseasesChallenges and future directionsReferencesFurther reading
Understanding rare diseasesRare diseases affect less than 5 people out of 10,000. However, this still amounts to about 7% of the world's population, with over 10,000 such conditions. Almost all are genetic in origin, with a few being autoimmune or infectious.
Most such patients undergo a diagnostic and therapeutic odyssey involving extensive and prolonged testing and multiple consultations. Only about 5% of rare diseases are currently treatable, the rest being "orphan diseases." However, precision medicine could provide an answer to this problem.
Image Credit: TanyaJoy/Shutterstock.Com
Precision medicine and rare diseasesPrecision medicine may be described as treatment tailored to the individual patient, based on detailed data about the patient coupled with reasoning back to the root cause at the molecular level. It aims at maximum therapeutic efficacy and minimal drug toxicity for all diseases. It accounts for inter-individual genetic variation that makes each person respond differently to a given disease or its treatment.
Genetic and molecular profiling Personalized diagnosticsAdvances in genomic sequencing, data science, imaging techniques, and genetic diagnosis have made it feasible to study orphan diseases in individual patients or small numbers of patients with a single rare disease. The development of precision medicine added economic and scientific value to investments in this field.
With rare diseases, identification of the molecular pathology, whether an abnormal gene or metabolic pathway, occurs simultaneously with the diagnosis. This should theoretically facilitate treatment since all that is needed is the correction of the single molecular flaw.
The challengeTraditionally, pharmaceutical research has focused on finding and developing commercially viable treatments that benefit large groups of people, thus excluding people with rare diseases. Few rare diseases have at least one or two approved treatments, leaving a large and untapped market for personalized therapies - mostly gene and cell therapies.
The promiseWhole-genome sequencing and whole-exome sequencing have overcome some important limitations of earlier genomics platforms, enabling the identification of many more pathogenic genetic defects, while RNA sequencing extends its reach.
Still, vast regions of non-coding DNA may contain pathogenic mutations, including regulatory elements, the 5′ untranslated region (5′UTR), and epigenetic modifications. Genome-wide association studies (GWAS), along with transcriptomics, have helped identify genotype-phenotype associations.
Large datasets and data-sharing networks are vital to identifying rare disease gene variants. In the USA, the NIH Undiagnosed Diseases Network (UDN) used an earlier program's searchable clinical and exome sequencing database to help patients undergoing a diagnostic odyssey reach a diagnosis while gathering valuable data. The UDN assessed over 1,000 patients with one week of hospitalization, diagnosing over 200 very rare diseases and discovering new diseases.
This has been extended to UDN International at present, one of several international organizations such as Care-for-Rare, REACT, and IRDIRC that help children with rare diseases.
Tailoring treatments for rare diseases Customized therapiesRare disease researchers use gene knock-out and drug repurposing screens in cell lines, tissue models, or animal lines to understand how mutations and drugs affect different cell types, including safety, tolerability, and bioavailability thresholds. This not only identifies diverse drug and gene targets but also allows for optimal treatment design in orphan diseases.
Success stories 1. SMAThe number one cause of death in babies worldwide is spinal muscle atrophy (SMA), caused by defective SMN1 genes leading to dysfunctional survival motor neuron (SMN) protein. This causes motor neuron breakdown and paralysis.
The first approved (2016) therapy for SMA is an ASO called Spinraza (nusinersen), which reduced deaths and the need for ventilation among SMA children. Injected intrathecally, Spinraza rescues motor neurons by promoting the production of functional SMN protein. Gene therapy is in the pipeline, and almost all other therapies are being developed.
2. Other neurological syndromesMila Makovec, in Colorado's Longmont, had Batten's disease and was rapidly deteriorating when she was put on a personalized nusinersen-like ASO, Milasen, starting in January 2018, to reactivate the single normal copy of the gene that she possessed. Within a month, her seizures were reduced by 50%, but she remains severely disabled.
Susannah Lorem had a rare genetic mutation, KIF1A, causing progressive, debilitating disease. The firm nLorem provided a personalized ASO free for life, starting October 2022.
3. DuchenneHereditary muscular disease called Duchenne muscular dystrophy (DMD) causes progressive muscle weakness caused by abnormalities in the dystrophin (a muscle protein) gene. It affects less than one in 6,000 male babies each year.
Potential therapies for DMD include ataluren, a small molecule that causes exon skipping. This could reverse the effect of a nonsense mutation disrupting dystrophin synthesis. That is, it skips a premature stop codon, allowing dystrophin gene transcription.
Sarepta Therapeutics has launched a one-time gene therapy for DMD that enables functional dystrophin synthesis. However, adverse effects, such as acute severe liver injury, myositis, and myocarditis, have been reported during the clinical trials, and a post-marketing trial is going on.
Investigational gene therapies from Pfizer are showing immense promise in DMD, with improvements lasting about 3-5 years.
4. Cystic FibrosisCystic fibrosis (CF) patients rarely live beyond early childhood. Though discovered in 1980, the CFTR gene has 2,000 pathogenic variants, making gene therapy an unsolved challenge in this case. Small-molecule drugs called CFTR modulators have been launched to correct defective CFTR protein function.
An oral drug, Trikafta, combines 3 CFTR modulators, reversing the effects of 178 different CFTR mutations. It may prolong survival in about 90% of CF patients.
The average CF patient lives ten times as long today as in any previous era, with a lifespan extending into the fifties. Notably, this is also because of intensive collaborative research resulting in better airway and nutritional management and improved antibiotic therapy, besides the CFTR modulators.
Challenges and future directions Overcoming hurdlesEthical principles still being discussed include the high cost of treating a single individual vs the cost of treating large numbers with readily available drugs. Other questions include the type of evidence needed for drug approval in humans and how to assess its efficacy.
There are nowhere near enough researchers to make custom drugs for all who might want them. And even if there were, who would pay? Unfortunately, that leaves it to families," says Dr. Steven Joffe, a medical ethicist at the University of Pennsylvania.
Since the Orphan Drug Act of 1983 became law in the United States, research into rare disease therapies has accelerated. The key shift is in value, making rare disease research a booming industry, with the market expected to grow by over 10% every year.
The large market base, plus the incentives from government and private investors such as early access, expanded access, accelerated approval, and extended patent rights programs, coupled with the fact that cell and gene therapies are at the heart of treatment for rare diseases, have powerfully stimulated research and development. In fact, these treatments are readily commercialized despite the small number of patients.
Drug repurposing studies identified the already approved drug epalrestat as a potential therapy for the rare disease PMM2-CDG, a glycosylation disorder. This was followed by a successful trial in the index individual, and larger trials are ongoing.
Rational therapeutic design is a tool to identify molecules that reverse the undesirable impact caused by a pathogenic genetic variant. This helped to identify low-dose ketamine as a potential therapy for a rare disease, ADNP syndrome, part of the autism spectrum disorder.
Precision Medicine in the Era of Rare, 2024Play
This method includes enzyme replacement in cases of metabolic errors like Gaucher's disease, antisense oligonucleotides (ASO), tiny corrective DNA bits for spinal muscular atrophy (SMA), small-molecule drugs for cystic fibrosis, and cell or gene-based therapies like stem cell gene therapy for adenosine deaminase deficiency.
Advances in stem cell research help assess individual responses to drugs and identify specific mutations that respond to potentially engineered therapies. This will maximize the odds of obtaining the desired response in clinical practice.
CRISPR gene editing-based therapies to eliminate pathogenic genes with point mutations as in sickle cell disease, and viral gene delivery vectors, are being investigated. Many issues remain to be overcome before their clinical launch.
Using sophisticated data analytics and artificial intelligence (AI) on large datasets of people, either orphan disease patients or related in some way, firms have helped educate and sensitize patients and healthcare providers in the most relevant ways. Such data can help identify high-risk regions or populations, increasing by up to 40% the number of potential patients found.
Using real-world data from large datasets, firms can take advantage of accelerated approval programs for orphan drugs by showing associations between rare diseases and life-threatening outcomes, which could not be proved from the small number of patients available by traditional methods.
Digital technology, including mobile apps, can be leveraged to educate and support patients and caregivers after the diagnosis. It can help HCPs track symptoms and optimize treatment schedules for such patients.
Pharmaceutical companies may invest in such support services in return for real-world information on how their therapies affect the patient. The high costs of treatment, coupled with the need for frequent traveling and doctor appointments, are daunting for many such patients, presenting another opportunity for health investors to step in.
ReferencesMental Health Challenges Faced By Children With Cystic Fibrosis Are The Focus Of A Major, Multi-site Study Led By UB
UB team has been instrumental in identifying and addressing how a person's mental health affects disease progression and outcomes in cystic fibrosis
Release Date: September 16, 2024
BUFFALO, N.Y. — A University at Buffalo psychiatrist who has played a critical role in getting mental health screening and treatment integrated into routine care for adults and adolescents with cystic fibrosis (CF) has been awarded $3 million from the Cystic Fibrosis Foundation to focus on the mental health of children with the disease.
Led by UB and launched this summer, the new study is an outgrowth of The International Depression Epidemiological Study (TIDES), which began in 2014 and was the largest study of mental health in adolescents and adults with CF. As a result of TIDES, annual screening for depression and anxiety is now part of routine CF care for nearly 90% of adults and adolescents with CF in the U.S.
"That's the goal of this new study, which we are calling TIDES 2.0," says Beth A. Smith, MD, principal investigator, interim chair of psychiatry in the Jacobs School of Medicine and Biomedical Sciences at UB, medical director of the Children's Psychiatry Clinic in Oishei Children's Hospital and founding chair of the Cystic Fibrosis Foundation's Mental Health Advisory Committee. "It will allow us to take what we have done nationally and internationally for adolescents and adults with CF and do it for children from 18 months up to 11 years old."
The study will evaluate the national prevalence of mental health concerns in children with CF under 12 years of age. It will identify the best ways to screen for mental health issues in these children, and it will characterize those issues most often seen in children being treated with the new therapies that have essentially revolutionized CF. It will identify potential risk factors and likely lead to the adoption of new international guidelines on mental health screening for children with CF, just as the original TIDES did.
Often diagnosed in infants, cystic fibrosis is a rare, chronic disease without a cure. A progressive, genetic disease, it affects the whole body, including the ability to breathe and digest food. Managing the disease is complex, and people with CF can spend several hours a day doing treatments to clear airways of mucus and treat other complications; some individuals eventually require a lung transplant.
In a small study Smith and her colleagues published in 2010, they found that children with CF as young as 7 years old start to have depressive symptoms.
Dramatic improvements
Fortunately, the prognosis for people with CF has improved dramatically in the past 20 years. That's due to improvements in multidisciplinary, specialized care, as well as the development of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies, which precisely correct the malfunctioning protein that is made by the CFTR gene. UB and Oishei researchers have been at the forefront of this research; in 2009 they enrolled the first U.S. Patient in a multisite clinical trial of these drugs.
Whereas in the 1950s, when children born with CF rarely lived long enough to attend elementary school, today, many people with CF grow up, marry, have families and live into retirement.
The impact these pharmaceutical advances have had cannot be overstated, but the story of the disease has grown more complicated.
Previous studies at UB and elsewhere have shown that depression in people with CF is linked with worse health outcomes, including decreased lung function, lower body mass index, increased exacerbations and hospitalizations, and increased mortality.
In a small study Smith and her colleagues published in 2010, they found that children with CF as young as 7 years old start to have depressive symptoms. "Kids become sad and irritable, they start to have a lot of negative thoughts about their lives, they notice that they're different from other kids," Smith says.
Googling one's disease for example, only intensifies those feelings. "Even though life expectancy has improved so much, there are a lot of comorbidities now that people are living longer," says Smith. "They have much higher rates of colorectal cancer, they get CF-related diabetes because their pancreas gets bogged down, and boys find out they might be sterile. There's just a lot that gets unfolded over time for these young kids."
Parents, of course, are also deeply affected and their concerns can, in turn, affect the child. So, Smith says, it is critical to identify and address mental health issues early on.
Danielle Goetz, MD, director of the Cystic Fibrosis Center of Western New York at Oishei Children's Hospital and clinical associate professor of pediatrics at UB is a co-PI on the grant with Smith.
Changing the trajectory
"Looking back on when I first began working with patients with CF in the early 2000s, I think if mental health screening had been more prominent and we had been addressing it in a different way, maybe we would have been able to change some of the patients' trajectories," she says.
In a previous study, Smith and colleagues found that people with CF with chronic depressive symptoms who had not received treatment were more likely to die than those who had had their depression addressed. "It's not that the other patients didn't have depression," she says. "They did, but it was addressed."
Changing those trajectories is part of Smith's mission with the new grant focused on children. "Can we change these trajectories if we treat the depression and treat it well and help with developing coping skills and disease self-management? Can we change the outcome so a positive depressive screening in someone with CF isn't associated with a doubling of the risk of mortality?"
Part of the care team
One key to doing that requires that the entire CF care team be committed to including mental health screening as part of standard patient care. Danielle M. Goetz, MD, director of the Cystic Fibrosis Center of Western New York at Oishei Children's Hospital, clinical associate professor of pediatrics and the leading CF pulmonologist as well as a co-PI on the new grant, plays a critical role.
"The pulmonologists are so important," says Smith. "They run the clinics; they're the boots on the ground. As a mental health clinician, I can say that mental health screening is important, but it won't happen unless the pulmonologists understand that this is important to total CF care. At our clinic, Dr. Goetz has been foundational to making sure this study works."
TIDES 2.0 will enroll patients at the Cystic Fibrosis Center of Western New York at Oishei Hospital in Buffalo and at 15 other sites nationwide including Massachusetts General Hospital/Harvard Medical School and the Johns Hopkins University School of Medicine.
People interested in enrolling in the study should contact Smith at balucas@buffalo.Edu or research coordinator Julianne Hergenroder at jhergenroder@upa.Chob.
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