![BSGCT [Development]](https://cjamwebdemo.co.uk/wp-content/uploads/2025/01/BSGCT-Logo-2024-UPDATE.png){kind=logo}
What is cell therapy?
The human body contains over 200 different specialised cell types, such as muscle, bone or brain cells. These cells carry out specific functions within the body, necessary for the health of an organism. Injury, disease or ageing can lead to the loss of specialised cells from the body. In many cases, such loss is irreversible, meaning that the diseased or lost cells can no longer be replenished by healthy ones.
Cell therapy aims to introduce new, healthy cells into a patient’s body, to replace the diseased or missing ones. A challenge for this type of therapy is having enough cells for transplantation into a patient. This is because specialised cells, such as brain cells, are difficult to obtain from the human body. Also, specialised cells typically have a limited ability to multiply, making it difficult to produce sufficient numbers of cells required for certain cell therapies. Some of these issues can be overcome through the use of stem cells.
How are stem cells used to develop cell therapies?
Stem cells are unspecialised cells that have the ability to develop into other functional cell types. Importantly, some types of stem cells can be grown outside of the human body, thus allowing the production of a large number of cells required for successful applications of cell therapy in medicine. Two main types of stem cells are being explored in the context of cell therapy: pluripotent stem cells and tissue-specific (also referred to as adult) stem cells.
Pluripotent stem cells can produce any cell type in the human body. Therefore, pluripotent stem cells provide a potential source of cells that are otherwise inaccessible or present in low numbers in human bodies. They can also be maintained and multiplied outside the human body for extensive periods of time. Depending on their origin, two types of pluripotent stem cells can be distinguished: embryonic stem cells and induced pluripotent stem cells. Embryonic stem cells are derived from early embryos, whereas induced pluripotent stem cells are derived by using a method called ‘reprogramming’, which turns specialised cells to cells very much like embryonic stem cells.
Unlike pluripotent stem cells which have the ability to give rise to any human cell type, tissue-specific stem cells give a much more limited repertoire of functional cell types. For example, blood stem cells give rise to other types of blood cells, but do not typically produce cells found outside of the blood system.
To obtain specialised cell types, either pluripotent or tissue-specific stem cells are grown in a laboratory and treated with cocktails of molecules, which provide signals for their development into functional cells.
Have cell therapies been successfully used?
Some cell therapies have been successfully used for many years now. The oldest example is the bone marrow transplant, which is routinely used in medicine to effectively treat certain diseases of the blood and immune system, such as leukaemia, lymphoma and myeloma. The bone marrow transplant contains blood stem cells which can replenish the blood and immune system upon transplantation into the recipient. This type of stem cell treatment has provided an important proof-of-principal for using cell therapies to treat patients.
More recently, stem cells from the eye (limbal stem cells) have also been used to treat eye injuries. In some cases, stem cells are first modified by gene therapy to correct the mutation causing the disease. Once the disease-causing mutation is corrected, the cells are delivered to patients to repopulate the diseased areas of their body. This so called combined cell and gene therapy allowed the development of therapies for blood disorders, including some types of leukaemia, lymphoma, severe combined immunodeficiency and β-thalassemia.
What is on the horizon for the cell therapy applications?
The ability to turn human stem cells into specialised cell types, such as cells of the brain, eye or pancreas, has opened up possibilities for developing treatments for many degenerative diseases. For example, several clinical trials are currently under way to treat Parkinson’s disease using pluripotent stem cell-derived brain cells. Parkinson’s disease is caused by the loss of a particular brain cell population that produces the chemical dopamine. The loss of these cells from the area of the brain called the substantia nigra leads to movement disorders, tremors and muscle rigidity. To replace the missing cells, scientists are deriving dopamine-producing brain cells from human pluripotent stem cells. The stem cell-derived brain cells are currently being tested in clinical trials to check whether they eradicate the symptoms of the disease. Similarly, scientists are testing the utility of using stem cell-derived cells of the eye to treat some blindness-causing diseases, such as age-related macular degeneration.
For cellular therapies to be a clinical success, it is important to have well-established procedures for creating the desired cell types in required quantities. It is also important to ensure that the transplanted cells can survive upon transplantation into the patient and integrate into the body to perform their functions. It is also important that the transplanted cells do not multiply too much, as that could create tumours in patients. This is why rigorous testing has to be done before cellular therapies become available to patients.
What is gene therapy?
DNA acts as a blueprint, providing all the information needed for building our proteins. Variations in DNA affect us all, but luckily most changes in our DNA are benign. A recent breakthrough study analysed the protein-coding ‘blueprints’ of more than 60,000 different people and identified a huge range of genetic variants that don’t cause any disease. You can read more about that study here.
However, some variants in our DNA can mutate, disrupt or delete important genes, leading to a disease or disorder. Many genetic disorders result in a wide variety of symptoms, often with serious health consequences. Many genetic disorders are also rare. Because of this, very few rare genetic disorders have treatment options that are curative, or even effective. Gene therapy has the promise of being a one-time, disease modifying treatment. If there is a broken gene, we can provide a working copy of that gene and fix the problem in the cells at a fundamental level.
How do we get that gene to the appropriate cells?
Gene therapy relies, mainly, on the use of viruses (also called viral ‘vectors’) to deliver the genes into the cells of patients. Viral-based gene therapy is often regarded as a ‘one-time treatment’ because repeated administrations are not effective. This has stimulated significant effort to develop non-viral gene therapy vectors for conditions that will require repeat delivery.
A flurry of gene therapy clinical trials in the late 1990’s and early 2000’s, driven by the progress of the Human Genome Project, used viruses to deliver genes to patients. Despite some initially promising results, the death of a patient and several cases of leukaemia revealed major problems with the types of viral vectors being used, setting the field back.
The development of safer viral vectors has been a major reason for the resurgence of gene therapy in recent years. New, improved lentiviral and adenoviral vectors have been shown to be safe and effective in preclinical and clinical settings. The emergence of adeno-associated virus (AAV) as a delivery system for gene therapy has proved to be a valuable tool for the field.
Gene therapy success stories
In one of the most striking recent success stories, AAV was used to deliver a gene therapy to treat children with Spinal Muscular Atrophy type 1 (SMA1). SMA1 type 1 is a progressive and severe motor neuron disease caused by mutations in a single gene, SMN1. Children either die or require mechanical ventilation by 2 years of age. Delivery of a functional copy of the SMN1 gene to a group of 15 children resulted in profound improvements. As of 2019, all the children in this first trial are still alive, all are breathing without a ventilator, two can even walk, emphasising the impact of the therapy as a truly disease-modifying treatment. You can read the 2017 published study here.
Gene therapy has now been shown to be effective tackling several, very different disease indications. To treat haemophilia, the delivery of Factor XIII or Factor IX as a gene therapy has been shown to significantly reduce bleeding in patients, the requirement for Factor XIII or IX infusions, and the number subsequent hospital visits. Gene therapy to treat children with epidermolysis bullosa, a severe and previously untreatable skin condition, was able to reconstruct 80 percent of a boy’s skin, including his arms, legs, and back; a profound improvement to the condition. Luxturna has been approved as the first ever gene therapy to treat a genetic disorder that causes blindness. A single injection in each eye (delivering the RPE65 gene) can improve vision in patients for more than three years.
These are just some examples. Many other gene therapy clinical trials are underway, and many of these target rare diseases (some very rare), where there are few current treatment options. You can go to the clinicaltrials.gov site to see how many gene therapy studies are currently active.
Gene therapy going forwards
With so many different disease indications, targeting the appropriate cells and regulating expression of the gene therapy (the ‘transgene’) is essential. Cutting edge research has provided the field with viral vectors and genetic regulatory elements that provide more specificity, targeting gene therapies towards the most appropriate cells in the body and regulating gene expression to ensure levels are not too high, or too low. This might mean, for example, that a gene therapy could be engineered to target and ‘switch on’ in brain cells but not in liver cells.
The viral and genetic toolkit available to researchers, and the success of recent patient trials mean that gene therapy is now a clinical reality. The SMA1 trial prompted the FDA to approve and ‘fast track’ that drug, now called Zolgensma, to the market. Luxturna, for retinal dystrophy, has also been approved and is on the market.
The next few years will be crucial to see how gene therapy is adopted into the clinical realm. Different healthcare systems will need to find ways to deal with these novel drugs, because it will undoubtedly be an expensive treatment option. However, it has the promise of being a one-time fix, unlike most conventional drugs. Cost-benefit ratios are likely to be at the forefront of developments, in addition to the clinical impact as we find out how effective and long-lived these therapies can be.