Overview

Fanconi anaemia (FA) is a rare inherited disorder primarily characterised by bone marrow failure and affects an average of 1 in 136,000 people.¹ This condition not only leads to a deficiency in blood cell production but also significantly increases the risk of developing blood disorders, heightens susceptibility to infections, and raises the likelihood of cancer development.² FA is caused by mutations in Fanconi anaemia complementation (FANC) genes, which are essential for the survival of different blood cells. FA is inherited in an autosomal recessive manner, meaning that an individual must inherit two mutated copies of the gene (one from each parent) for the symptoms to manifest.^1,2

Several methods are currently used to treat and manage FA, and they include some of the following: 

• Blood transfusions
• Androgen therapy 
• Hematopoietic stem cell transplantation
• Surgical therapy 
• Synthetic growth factors¹

Gene therapy is a potential treatment for FA that involves altering genetic material to address the underlying issue, in this case, mutations in the FANC genes.³ While gene therapy has not yet demonstrated a complete cure for FA, ongoing research aims to achieve this goal.¹

Pathophysiology of Fanconi anemia

Molecular mechanisms 

Mutations in the FANC genes lead to Fanconi anaemia by impairing the cells' ability to repair DNA damage. In approximately 80% of FA cases, mutations occur in the FANCA, FANCB, or FANCC genes.^1,3 These genes are essential for producing proteins that make up an essential complex of proteins, the FA core complex. The proper assembly of this core complex is crucial for effective DNA repair. When mutations disrupt the formation of the core complex, the repair of DNA damage is also impaired.¹ The defects in the DNA repair mechanism caused by such mutations increase the likelihood of clinical manifestations. 

Clinical manifestations 

The manifestations of Fanconi anaemia can vary widely among individuals and can be categorised into three main groups: haematological symptoms, physical abnormalities, and an increased risk of comorbidities, particularly cancer.

Haematological symptoms 

Haematological symptoms refer to manifestations associated with blood disorders. In FA, the most common haematological symptoms are listed as follows: 

• Bone marrow failure: Associated symptoms manifest as a result of the following
  • Anaemia: low blood cell count leads to fatigue, pallor and shortness of breath
  • Leukopenia: reduced white blood cell count increases the susceptibility to infections 
  • Thrombocytopenia: low platelet count results in bleeding tendencies and easy bruising^1,2
• Pancytopenia: the direct reduction in red blood cells, white blood cells and platelets due to bone marrow failure⁴

Physical abnormalities

Physical abnormalities in individuals with FA manifest as congenital malformations or genitourinary anomalies.

• Congenital malformations
  • Short stature: Individuals may have a shorter height than average 
  • Skeletal abnormalities: Limb malformations, such as radial dysplasia and skeletal deformities 
  • Skin pigmentation changes: Café-au-lait spots and hyperpigmented lesions^1,2
• Genitourinary anomalies
  • Renal abnormalities: structural defects in the kidneys and urinary tract 
  • Reproductive system issues: reduced fertility or structural abnormalities of the reproductive organs⁵

Increased risk of cancer 

Cancer is a common co-occurrence in individuals with FA. This often includes haematologic cancers such as leukaemia, particularly acute myeloid leukaemia (AML), which is prevalent among FA patients. Additionally, people with FA are at an increased risk of developing solid tumours, with a notably higher incidence of head and neck cancers.⁶

Basics of gene therapy

Definition and principles

To understand gene therapy, it is first essential to understand the function of a gene. A gene is a segment of genetic material that encodes a specific protein. Mutations are alterations in this genetic code.⁷ These changes can often lead to non-functional proteins and subsequently disease. In Fanconi anaemia, for example, mutations in the FANC genes result in defective DNA repair mechanisms.⁷

Gene therapy is a medical technique that involves modifying or manipulating genes within a person’s cells to treat or prevent disease. This approach aims to correct the underlying genetic causes of disease and offer a potential cure for conditions that are difficult to treat otherwise.⁸ Gene therapy has demonstrated its effectiveness and success in treating or curing various conditions, including:

• Immune deficiencies 
• Hereditary blindness 
• Haemophilia 
• Lipid metabolism disorder
• Cancer⁹

Gene therapy involves several crucial steps for achieving a healthy gene in the target cells.¹⁰ This can be achieved through one of three methods: gene addition, gene silencing or gene editing. 

Gene addition 

Gene addition is a therapeutic approach that involves introducing a functional copy of a gene into a patient’s cells to compensate for a defective or missing gene. This type of therapy is commonly used when a mutation causes a complete loss of function, where the original gene’s ability to produce the necessary protein is impaired or absent.¹⁰

Gene silencing

Gene silencing is another therapeutic approach that aims to reduce or eliminate the expression of a specific gene. This method is useful when a gene’s activity is harmful or contributes to disease. An example of this would be in cancer, where genes contain “gain-of-function” mutations.

Gene editing 

Gene editing is a more sophisticated and precise technique used in gene therapy, and it can directly alter the DNA sequence within a cell. This is done by either correcting, replacing, or deleting specific genes to treat or prevent disease.

Gene therapy for Fanconi anaemia: Mechanisms and approaches 

Overview of gene therapy strategies for FA

Research has demonstrated that gene therapy can alleviate symptoms related to bone marrow failure in FA patients. However, whether gene therapy can fully restore the affected molecular pathways and provide a complete cure remains unconfirmed.¹¹

Gene therapy for FA employs several strategic approaches to correct the underlying defects in the FANC genes caused by mutations. Both gene addition and gene editing methods have shown some success. However, a 2022 study indicates gene editing techniques to be more effective and potentially safer.¹⁰

Gene editing and CRISPR/Cas9

CRISPR/Cas9 is a revolutionary gene-editing tool that has shown promise in treating genetic disorders like FA. It allows scientists to make precise changes to the DNA sequence of a gene. For FA, CRISPR/Cas9 can be used to edit and correct specific sequences in mutant FANCA genes. A study demonstrated that this approach successfully restored the correct function of the FANCA gene.¹¹

Delivery methods

While it is promising that studies are demonstrating the potential of gene therapy, its effectiveness hinges on successfully delivering the therapeutic intervention to the target cells. Most gene therapies require a vector to transport the modified genes. In the case of edited FA genes, a virus often serves as the vector, delivering the corrected genes to the specific target cells.¹¹

Lentiviruses are the most commonly used vectors for gene therapy because they effectively target many cells with non-functional FANC genes. They are highly efficient in delivering the therapy and demonstrate stable integration. However, there is the risk that they could cause further mutations.¹²

Benefits and risks of gene therapy for Fanconi anaemia 

Potential advantages

A major benefit of gene therapy is its ability to directly target and correct the root cause of FA, the mutations in the FANC genes, rather than merely managing the symptoms. This approach is personalised and can be tailored to treat individuals with different mutations. By restoring the function of the FANC genes, gene therapy can alleviate symptoms associated with bone marrow failure, significantly improving the quality of life.

Unlike current treatments, which primarily focus on symptom management, gene therapy has the potential to provide a cure or a long-lasting solution, thereby reducing the dependency on other management techniques. Correcting the mutations in the FANC genes would result in a functional DNA repair mechanism, thereby reducing the risk of cancer.

Risks and ethical considerations 

One of the risks associated with gene therapy, both for Fanconi anaemia and in general, is the potential for unintended genetic alterations to non-target genes. This can lead to serious issues, such as the creation of new mutations and an increased risk of cancer. Additionally, because gene therapy is a relatively new technique, its long-term effects are still not fully understood.

Gene therapy is also a highly personalised procedure, making it very expensive. Availability is limited, and determining who should have this treatment poses a significant challenge for public healthcare systems.

Summary 

Gene therapy for Fanconi anaemia (FA) represents a promising treatment approach directly targeting and correcting the underlying genetic mutations in the FANC genes that cause the disease, rather than merely managing its symptoms. This rare inherited disorder, characterised by bone marrow failure, increased susceptibility to infections, and higher cancer risks, currently relies on treatments like blood transfusions, androgen therapy, and stem cell transplantation. 

Gene therapy, employing techniques such as gene addition and gene editing with tools like CRISPR/Cas9, aims to restore the proper function of defective genes. While gene therapy has shown potential in alleviating FA symptoms and reducing cancer risk, it poses challenges, including unintended genetic alterations, high costs, and limited accessibility. Ethical considerations around long-term effects and equitable access further complicate its implementation in public healthcare systems.