Cystic fibrosis: how could gene and cell therapy help?

Cystic fibrosis is one of the most common genetic conditions, with a frequency of between 1 in 3000 to 6000 in European populations. It derives from mutations in a single gene: the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Carriers will have just a single mutated copy of this CF-causing gene. A full diagnosis of CF is made when a copy of a mutated gene is inherited from both parents. Researchers have identified more than 2,000 CF-causing mutations in this CFTR gene giving rise to copious combination potentials. It is important to note that different mutations, or combinations of mutations, impact on the severity of disease. Modulator therapies, which target the faulty membrane channel, have had a significant impact for CF patients who have inherited the most commonly occurring mutations. However, approximately 15% have rarer mutation types, meaning they are unable to benefit from these and require alternative methods of treatment.

The CFTR gene makes a protein that functions as a channel in the cell membrane, allowing the movement of salt and water into and out of the cell. The inability to regulate this transport of salt and water into and out of the cells lining our airways causes people with CF to harbour thick, sticky mucus in their lungs.  Lifetime daily treatment with medication and airway clearance techniques is burdensome and exhausting. While these treatments can slow decline in lung function, they do not prevent repetitive lung infections which lead to chronic lung disease and reduced survival in people with CF.

Researchers are working on a range of therapeutic approaches that address the underlying cause of the condition and could potentially treat all people with CF, regardless of their type of mutation. This includes gene therapy and gene editing options that seek to either:

• deliver a working copy of the gene that can generate functional CFTR protein or
• change the existing gene with a mutation back to the correct sequence through editing.

A number of these approaches have already been tested in clinical trials, and others are currently being evaluated in ongoing clinical trials.

One of the biggest challenges is developing vectors that can deliver the therapy to enough of the affected cells in the lungs. A number of approaches currently in development use modified viruses or types of nanoparticles that can carry genetic material such as DNA or mRNA into the cells. The cells that require therapy have a limited lifespan and many of the proposed approaches have limited duration. Depending on the vector, the effect can last from weeks to months. As a result, the therapy would need to be applied repeatedly. This presents another challenge: the immune system may develop antibodies to the viral vector following the first treatment. If the therapy is readministered, the immune response to the viral vector may render it ineffective. Safety is also a challenge in the context of vectors that integrate into host DNA and have the potential to cause mutations (insertional mutagenesis).

• Mutations in CFTR affect the production and availability of digestive enzymes. The thick mucus in the digestive tract may prevent digestive enzymes (produced in the pancreas) from reaching the gut. This results in malabsorption and malnutrition. Most people with CF have to take enzyme replacement supplements with all food to aid digestion and nutritional absorption. In addition, the build-up of enzymes in the pancreas can cause inflammation, which damages the pancreas. The damage to the pancreas is known to cause CF-related diabetes (CFRD), seen in approximately one-third of people with CF.
• 10-15% of newborns with CF suffer from severe intestinal blockage, termed Meconium ileus (MI). These infants cannot have normal bowel movements until the blockage is resolved. This causes issues with feeding, swelling (distension) of the abdomen, and may cause inflammation of the surrounding tissues. MI may require surgery to remove the blockage. Similar episodes can affect people with CF throughout their lives, presenting as distal intestinal obstruction syndrome (DIOS)

Current daily treatment regimes include the following:

• Physiotherapy and Airway Clearance Techniques (ACT):  This helps loosen and clear the thick mucus in the lungs.

• Enhanced diets and other nutritional interventions: These help to maintain a healthy weight and nutritional status.  This can be challenging for people with CF due to the lack of the digestive enzymes that break down fats, proteins and carbohydrates and release the nutrients that the body needs. Poor nutritional status is associated with poorer lung health and bone density. In addition, long-term use of antacids often form part of the treatment regime for people with CF.

• Pancreatic Enzyme Supplements: These replace the missing enzymes that are not being supplied to the gut, due to obstruction in the pancreatic ducts.  Without enzymes, nutritional and oral medicinal absorption are compromised. 

• Inhaled/IV antibiotics: These are used primarily to prevent or control respiratory infections. Advances in antibiotic therapy for people with CF has been the main reason for the significant improvements in quality of life and survival over the last few decades. These can be administered either by inhalation or intravenously, depending on the individual circumstances, but with repeated use, antimicrobial resistance (AMR) is an increasing threat.

• Inhaled recombinant DNAse. These help break down the thick, sticky mucus in the lungs. The unusual stickiness of mucus in people with CF is partly due to a high concentration of DNA, which is released from certain immune cells (neutrophils) as they disintegrate. Using DNAse to break down these DNA molecules decreases the stickiness and viscosity of the mucus. This helps to clear mucus more naturally, or during physiotherapy or ACT.

   

• Modulator therapies: All of the treatments listed above can only treat symptoms of CF. CFTR modulator drugs, in contrast, tackle the underlying cause of the disease by helping the faulty CFTR protein work effectively. These drugs have been transformative for 80-90% of patients, stabilising health and leading to long term improvement in lung function, exacerbation frequency, weight and quality of life.  People with CF are learning to adjust their dietary and nutritional requirements, insulin requirements, along with nebuliser and ACT frequency.  However, it is estimated that 10-15% of people with CF worldwide are not able to benefit from these ground-breaking therapies due to the type of mutation they carry.  These drugs are also very costly, meaning that access through centralised healthcare systems is highly variable.

At time of writing (2024), two gene therapy approaches are currently in clinical trials.

The first of these (from 4D Molecular Therapeutics), uses a modified adeno associated virus (AAV) (Details of this Phase 1/2 trial are available here.)

The second (from Krystal Biotech) uses a vector based on a Herpes Simplex Virus-1 (HSV-1) (Details of this Phase 1 trial are available here  and here). 

Importantly, these viruses have been inactivated so that they are not able to replicate in the target cells and cause cell damage or loss. Both these vectors carry a healthy copy of the CFTR gene into the cells but do not insert into the host cell DNA. Instead the DNA remains in the cell nucleus, separate from the host chromosomes. This means the patient’s own DNA remains unaltered. However, it also means the effects of the therapy do not persist in the long term. This therapy would therefore need to be repeated, rather than being a ‘one-off- solution. 

At time of writing (July 2024), these trials are ongoing and do not have conclusive findings.

The Cystic Fibrosis Trust keeps an up-to-date list of ongoing trials in the UK. (Please note these trials are recruiting in the UK only.)