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Gene Therapy For Cystic Fibrosis

Parental Attitudes Toward Gene Therapy

CF Foundation | Emerging Genetic-Based Therapies for CF

Whilst scientists may argue that children should be included in gene therapy trials, there are no data to support the views of parents, who will need to give consent to their children participating in these trials. We therefore sought the opinion of parents of CF children on the question of conducting gene therapy trials in general and whether they would be willing to enrol their child/children in any such trial. The hospital ethics committee deemed formal ethical permission for this survey unnecessary. One hundred and sixty parents of children from our tertiary CF centre were sent an anonymised short questionnaire . The response rate was 48.8%. Families who responded had a total of 80 children with an age range of six months to 17 years. Eighty two per cent of respondents felt that gene therapy was the most important area of research in CF, with 56% of respondents hoping for a cure 31% expecting that it might improve symptoms but not cure the disorder 10% hoping for both, and 3% not sure. Ninety nine per cent of respondents felt it was ethically sound for children to be given the opportunity to be involved in gene therapy trials provided that they were carefully run, with safety issues as the priority. Ninety one per cent of families stated that they would consider consenting to their child taking part in a CF gene therapy trial. Four per cent said they would not consider consenting and 5% of families felt unable to make such a decision.

Understanding The Genetics Of Cystic Fibrosis

On the surface of each and every cell in a healthy lung there are proteins that form channels through which salt and water can pass. These proteins regulate how much of these substances enter and leave the cells to keep it functioning properly. The cystic fibrosis genetic mutations mean that the cells have an error in their instructions , so the protein is not made properly, or is not sent to the cell surface where it is needed. This causes many of the problems you can read about on our How CF affects the body webpage.

How Do Cf Gene Therapy Treatments Work

CF gene therapy treatments are still in development. Their aim is to deliver healthy copies of the CF gene to the lung cells to allow a healthy, working copy of the CFTR protein to be produced. If there are healthy copies of the CFTR protein, this means that the lungs would be healthier, reducing the symptoms of cystic fibrosis.

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Challenges Of Gene Editing For Cf

A major advantage of gene editing is that the changes that it makes to the DNA are permanent. People might require only one treatment with a gene editing tool to have a lasting effect on their disease. However, many challenges still need to be overcome before gene editing can be used to treat CF.

For example, gene editing tools can be customized to find a specific CFTR mutation, but there are many CF-causing mutations. Researchers are studying the effectiveness and efficiency of different techniques in the lab that would allow the correction process to fix anywhere from one mutation to all mutations.

Off-site edits also pose a risk. In theory, gene editing should be a very precise therapy, meaning that the gene editing tool should break the person’s DNA only at the site it was designed to find. For CF, the tool would be designed to find the site of the CFTR mutation.

In practice, gene editing is not perfect. Sometimes, gene editing tools break the DNA in the wrong place in the genome. An error like this could result in new mutations in other genes and cause unintended consequences, such as an increased risk for cancer . For this reason, each gene editing tool must be evaluated individually to determine whether it is precise enough to be used in patients.

Primary Human Bronchial Epithelial Cell Culture

In vivo Gene Correction of Cystic Fibrosis

For HBEC RNA samples, early passage primary HBEC cultures were grown in ALI culture conditions as previously described. They were expanded and allowed to differentiate while exposed to air apically until day 14. Cells were dissociated into single cells and collected in QIAzol lysis reagent and stored at 80°C until RNA purification. W1282X/W1282X HBEC cultures used for electrophysiologic analysis were similarly early passage and grown in standard published conditions.

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Projected Cost Of Gene Therapy For Cystic Fibrosis

Without any treatment on the market, we can only speculate about the expected cost of gene therapy for cystic fibrosis.

Here is a back-of-the-envelope calculation of a possible price tag for cystic fibrosis gene therapy.

There are three factors driving up the price of gene therapy. First one is the cost of a therapy development. It costs between $1B and $5B for a company to pass all regulatory approvals before a drug is brought to patients.

Second factor is small market size. Treatments for rare diseases can be sold to a small number of patients. With high development and regulatory costs, a pharmaceutical company needs to charge a lot from each patient to make their money back.

Third factor is the cost of production. It is much harder to produce viral particles packaged with DNA than to produce chemical molecules.

Current gene therapy treatments range in price from USD 2.1M for Zolgensma, $1M for Glybera, $850K for Luxturna, and down to $373K for Yescarta.

The good news is that technology becomes cheaper with time.

Regulatory process will get smoother with each new therapy entering the market.

Production of viral particles can be streamlined. Non-viral gene therapies based on nanoparticles are developed for the exact same reason of reducing production cost. Finally, cystic fibrosis is not as rare as some other rare diseases, so there will be a fair demand for the therapy once it becomes available.

Developing Gene Therapy To Treat Cystic Fibrosis: Challenges And Successes

More than 25 years after the gene for cystic fibrosis was discovered, there are signs that correcting this genetic deficit could soon be possible.

Gene therapy

Science Photo Library

A tiny globule of fat suspended in a fine mist makes its way along the branching passageways of a human lung. Deep in the lung the globule, called a liposome, nestles up against one of the cells lining the airway. Because the cell membrane is also made of fat, the liposome is able to pass through it, and spill its cargo into the interior of the cell: a string of DNA encoding a protein known as CFTR, which will enable the cell to make thin, watery mucus that helps keep the lung clean and healthy.

This is gene therapy for cystic fibrosis, a genetic disorder that causes serious lung disease. In a phase III trial published in 2015, the UK Cystic Fibrosis Gene Therapy Consortium, a group of scientists and clinicians from London, Oxford, and Edinburgh, reported that inhaling these liposomes every month for a year stabilised the lung function of individuals with cystic fibrosis. Meanwhile, lung function deteriorated slightly in the studys placebo group.

These are modest effects, as even the studys authors acknowledge. I think we need to improve on that before the therapy could be rolled out to clinical care, says Eric Alton, professor of gene therapy and respiratory medicine at Imperial College London and the consortiums coordinator.

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Zinc Finger Nucleases And Transcription Activator

Early developments of gene editing approaches included use of artificial restriction enzymes, Zinc Finger Nucleases and transcription activator-like effector nucleases , . These gene modification tools enabled precise genome editing through targeted nucleases cleavages and renewed hope for gene therapy. ZFNs are composed of specific pairs of oligos attached to a FokI restriction enzyme that facilitate a precise double-strand break at the target site . TALENs are composed of TALE repeats that bind and recognize extended DNA sequences and are also attached with a FoKI restriction enzyme to create a DSB . In both instances, the DSB induces DNA repair mechanisms by either non homologous end joining , or homology-directed repair . Neither ZFN and TALENs technology have been used in CF gene therapies and in the advent of CRISPR-Cas systems, gene editing using the latter tool is more flexible making it the editing tool of choice for many researchers. The specific requirement of a pair of ZFNs reduces the number of target sites that can be identified for gene correction. Moreover, the low binding affinity of the ZFN creates undesirable off-target mutations in the genome . TALEN has shown less off-target and better binding affinity than ZFN, however, the size for cDNA encoding a TALEN can be an issue for delivery into cells with a limited cargo size .

Table 1 Advantages and disadvantages of gene editing tools

Advantages Of Gene Therapy

Cystic Fibrosis Gene Therapy – Not As Easy as We Thought

The main advantage of gene therapy approach is that it deals with the root cause of the disease.

Traditional treatment of cystic fibrosis involves using antibiotics that treat lung infections, and removal of mucus. Both approaches do not address the underlying cause of the disease, and therefore need to be repeatedly applied during the life of a patient.

Cystic fibrosis is also a progressive condition, meaning that it gets worse over time. Most patients have shorter-than-average life expectancy and may die because of lung failure.

Gene therapy promise is that one day kids born with cystic fibrosis would get a one-off treatment and live a normal life like everyone else.

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Gene Therapy Still To Consider

To date, CF gene therapy clinical trials have not been conclusive, with a weak effect observed on CF patients lung function, associated with important immune responses, which may render the treatment ineffective. Moreover, as mentioned previously, the recent developments of effective drugs such as the triple combination elexacaftor/tezacaftor/ivacaftor, which greatly improves patients lung function and quality of life, has given rise to the idea that cystic fibrosis is almost cured. Thus, it is therefore legitimate to wonder to what extent gene therapy still has a place in the treatment of CF. However, it should be remembered that the drugs currently on the market still leave aside at least 10% of CF patients without curative treatment, as highlighted by the Cystic Fibrosis Foundation patient registry. In addition, current CFTR modulators are not well tolerated by all eligible patients and real-life studies show that numerous patients stop their treatment. Besides, we do not have enough hindsight to predict effectiveness of these promising drugs in the long term.

In conclusion, CF gene therapy still has a bright future ahead. The main current challenge is to circumvent technical problems of transduction encountered in the lung. If this happens one day, not only will CF be truly cured, but the gene therapy might also be applied to other lung genetic diseases.

Gene Therapy: Whats Up

Gene therapy consists of introducing a functional gene into host cells to replace a defective gene. Theoretically, this could be a perfect match for the needs of a monogenic disease as CF and could lead to a universal treatment for CF patients. Especially since Johnson and colleagues stated in 1992 that 610% of CFTR-corrected cells are sufficient to observe a therapeutic effect in vitro , we can speculate that correction of all CF airway cells may not be mandatory to observe the same effect in vivo. However, the race for CF gene therapy turned out to be more challenging than expected so far.

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Heterogeneity Of Cftr Expressing Cell Types In Lung

Gene therapies for CF lung disease will likely need to navigate complexities of CFTR biology and function in the lung. CFTR expression is highly regulated in specific cell types of the lung, each having its own potentially unique composition of channels and functions that coordinate clearance and innate immunity in the lung . In the proximal airways, CFTR protein and mRNA expression are very abundant in a small subset of columnar non-ciliated cells in the surface airway epithelium and submucosal gland duct and serous cells . In the more distal airways, CFTR expression is found at very high levels in respiratory bronchioles and a small subset of columnar non-ciliated cells in the terminal bronchioles . Recent studies using single-cell RNAseq are helping to better specify the CFTR expressing cell types in the airways and identified the ionocyte as the columnar non-ciliated cell that expresses approximately 50% of CFTR transcripts in the surface airway epithelium. Interestingly, little to no CFTR mRNA transcripts were detected in secretory and ciliated cell types . While human ionocytes may be a major source of CFTR expression in the proximal airway epithelium, they comprise only 0.5% to 1.5% of epithelial cells along the conducting airways.

Developing Gene Therapy For Cystic Fibrosis Sounds Easy In Theory

Developing gene therapy to treat cystic fibrosis: challenges and ...

Cystic fibrosis is a genetic condition that by now should have been treated with gene therapy:

First, the disease is caused by mutations in only one gene. The gene, called cystic fibrosis transmembrane conductance regulator gene, or CFTR, has been identified thirty years ago .

Second, all known mutations in CFTR are recessive. That means that adding a functional copy of the gene will cure the patients.

Finally, lungs are an organ that can be easily accessed. Gene therapy could be delivered to the lungs by inhalation.

Unfortunately gene delivery to the lungs turned out to be much harder than initially thought.

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Small Change Big Difference

The trial involved 116 participants, 62 of whom received at least 9 monthly doses of the therapy, while a control group of 54 inhaled saline solution. To gauge the effect on lung functioning, changes in the volume of air each participant could force out of their lungs in one second were tracked.

At the end of 12 months, those who had been breathing in the gene treatment had, on average, 3.7 per cent better lung function than those on the placebo.

While this is obviously not a home run, I do think the results are impressive. Im pleased that gene therapy has been shown to safely deliver statistically significant treatment effects, says Oli Rayner, who has cystic fibrosis and works as an advocate for those who have the disease in the UK.

Over the course of the year, the lung function of people in the treatment group seemed to stabilise, while the control group showed a steady decline in lung power.

The lungs of people with cystic fibrosis typically get worse at a rate of about 2 to 3 per cent a year, and Rayner says that a small change to this rate of decline could mean the difference between needing a lung transplant at the age of 60 instead of 40. That is a big deal it could mean a very different kind of life for them and those around them, he says.

New Models New Gene Editing Tools New Targets

One of the biggest challenges in generating treatment strategies for CF is the sheer number of CF-causing variants. Even among patients with the same variant, there are vast differences in severity of symptoms and responses to treatments. To date, treatment options for CF are mutation-dependent, and no viable options exist to universally address all CF patients. Though recent advancements in gene editing have fostered hope for personalized treatments, this is neither viable nor practical for treating all CF.

Recently, Kemaladewi et al. demonstrated a novel mutant-independent therapeutic approach to treat congenital muscular dystrophy type 1A . Using CRISPR, the feasibility of treating inherited diseases by looking beyond the singular disease-causing gene, and instead targeting compensatory modifier genes, was illustrated. In the context of CF, ion channels aside from CFTR have been implicated in CF disease severity and responses to modulator therapy. Therefore, targeting other ion channels known to also affect CF disease severity such as the sodium channel ENaC or alternative ion channels TMEM16A and SLC26A9 may need to be assessed to find effective therapies for all individuals with CF.

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Animal Models For Cf Gene Therapy

Animal models are indispensible when developing gene therapies. For gene therapy of CF lung disease, many questions can be addressed in animal models. These include identifying the necessary cellular targets, doses required to complement CFTR defects, and establishing the efficacy of gene delivery approaches in the hostile environment of the CF lung. To date, CF animals have been produced in mouse, rat, rabbit, zebrafish, ferret, pig, and sheep . Characterization of lung disease in CF rabbits and sheep has lagged behind the other species. While CFTR-null mice and rats do not acquire spontaneous airway infection, CFTRKO ferret and pig models recapitulate many features of the lung disease phenotype observed in humans with CF . However, these models also exhibit severe gastrointestinal and pancreatic disease at birth , which has limited their broad use in developing gene therapies. Despite these limitations, CF pigs have been successfully used to demonstrate efficacy of both lentivirus and rAAV-mediated in vivo CFTR gene therapy approaches .

Molecular Mechanism Of Cystic Fibrosis

CF Foundation | How Gene Editing Could Be Used for CF

Main symptom of cystic fibrosis is the formation of thick sticky mucus in the lungs. The mucus clogs airways, leading to difficulties with breathing and lung infections.

On a molecular level the disease is caused by a defect in cystic fibrosis transmembrane conductance regulator protein, also known as CFTR.

CFTR protein moves chloride ions across cell membranes to the cell surface. Chloride ions attract water, creating a salt-water balance. When CFTR protein is absent or defective, insufficient amounts of chloride ions and lack of water molecules lead to mucus formation .

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Why Has It Taken So Long To Get This Far

Gene therapies are difficult to develop. Working out how to get the new copies of the CF gene into the right cells is particularly hard. The GTC have tried two different ways of wrapping up the CF gene, to safely and effectively deliver the treatment inside lung cells. Clinical trials of their first product showed that gene therapy treatments could work to treat CF, but improvements were needed with the wrapper. A different wrapper was then used for their Wave 2 product. It is the Wave 2 product that BI will now take the lead on developing.


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