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How cell therapy differs from gene therapy

Anna David is a professor of fetal medicine at UCL, and a world expert on cell therapy. This article looks at cell therapy and gene therapy.
So we currently have funding from Horizon 2020, the European Commission to do a first in women trial of stem cells given to the foetus to treat a bone disease called Osteogenesis Imperfecta. So it’s a trial that will-, it is mainly a safety study but also will be able to have a look at efficacy and it is essentially trying to find out if you give Mesenchymal stem cells to a foetus that has a diagnosis of severe OI, will it improve their outcome? So currently in OI it’s rare but severe cases we probably see about one or two a year in the foetal medicine unit here at UCL. And babies are born with severe fractures. They might fracture fifty-hundred times a year.
They have problems with their breathing and the post-natal treatment is really palliative only. It tends to improve the amount of collagen that the babies produce but the collagen itself is not very good collagen. So the idea is that you give Mesenchymal stem cells, so foreign stem cells to the foetus in the womb when the diagnosis is made and that’s very easy to make on scan because you can see the bones are very, very short and they also fractured as well. And then you would confirm that with a molecular diagnosis done using an amniocentesis.
So if that worked that realy does open up a whole world of possibility because we are currently working on doing non-invasive prenatal testing diagnosis for OI at twelve weeks, very early on in pregnancy. So you can, if you look very carefully see fractures. It is very early but we might be able to do a maternal blood test finding this out. We think that if you go in earlier in the foetus you’ve got more efficacy, you get more stem cells per kilogram of foetus so you have better effect. The fractures won’t be quite as well developed. So you will have a better effect. So who knows?
Maybe it will be a while yet, probably five/ten years we will be making a diagnosis and treating the foetus quite early on. We really have to make sure that parents are not under a sort of therapeutic misconception. In other words they understand that there is a possibility it might do more harm than good. And so parents have made that decision, that they are committed to the pregnancy. Of course if it is found in the clinical trial that it’s beneficial then when you’ve got the data to show how beneficial it is you could then start saying to patients if it is available clinically there are now three options. One of them is to have no treatment, to accept and effected child.
The other one remains, if it is available where you are, to have a termination of pregnancy. Or thirdly, to have this treatment which may improve the outcome. Now of course we would need quite a few cases to be able to say how much the outcome was improved. And I think for very rare diseases that is going to be a real challenge. Particularly, if there is not much of a close link between the genotype and the phenotype. So with OI the phenotype/genotype, there is quite a bit of heterogeneity there. So it’s difficult to predict from the genotype and what you see in utero how they are actually going to do later on in life.
But you may say, “okay, we perhaps could convert your child to having fifty fractures a year to having one fracture a year.” And for parents and for patients that may be enough for them to say, “yes, I am going to go for it.” But I think whenever we are doing a clinical trial we have to be very careful to make sure we collect all the natural history data on the disease and then how the intervention effects it. Does it improve it? How much does it improve it by? And to be honest with the patients when we are saying “this is available, this is what it could do, do you want it?”

Prof Anna David leads a team of scientists and clinicians at UCL that are finding new and fascinating ways to treat diseases in the unborn.

Brittle bone disease

One such disease is also known as brittle bone disease, also known as osteogenesis imperfecta, which sadly occurs in about one in 20,000 births.

Brittle bone disease can be devastating for young children because their bones are prone to fracture multiple times. Affected children may also present with shorter height, breathing problems, neurological abnormalities, hearing loss or other complications. The fractures can be very painful and there is often a stark reduction in quality of life.

The reason why some babies are born with brittle bone disease is that they have a problem forming the connective tissue that is essential for healthy bone growth and development. Most cases are caused by mutations in the COL1A1 and COL1A2 genes, both of which code for type I collagen.

For the moment, there is no cure. Treatment is limited and patients rely on painful physiotherapy and symptom control.

What is cell therapy?

Cell therapy is the transfer of cells into a patient in order to improve or even cure a disease. The origin of the cells depends on the treatment. The transplanted cells are often a type of adult or fetal stem cell which have the ability to divide and self renews as well as provide cells that mature into the relevant specialised cells of the tissue.

A common form of cell therapy is bone marrow transplantation, which has been performed for over 40 years.

Several investigative protocols of cell therapy involve the transfer of adult T lymphocytes that are genetically modified to increase their immune potency and can self renew and kill the disease-causing cells.

Stem cells from umbilical cord blood and other tissues are being developed to treat many genetic diseases and some acquired diseases. Stem cells from the fetus may be better than adult stem cells; they divide more and differentiate better into the definitive cell type, for example, fetal liver stem cells produce much more bone than adult liver stem cells.

How are gene therapy and cell therapy-related?

Both approaches have the potential to treat the underlying cause of both genetic and acquired diseases by replacing the missing proteins or cells, and they may suppress the expression of proteins that are toxic to cells.

Whereas gene therapy involves the transfer of genetic material into the appropriate cells, cell therapy is the transfer of cells to a patient. Gene therapy involves the transfer of genetic material usually in a carrier or vector, and the uptake of the gene into the appropriate cells of the body. Cell therapy involves the transfer of cells with the relevant function into the patient.

Risks of cell therapy

Risks of cell therapy also include the loss of tight control over cell division in the stem cells. Theoretically, the transplanted stem cells may gain a growth advantage and progress to a type of cancer or teratomas, but this is only rarely seen in stem cell transplantation and has not yet been seen in fetal stem cell transplantation.

Since each therapy has its potential risks, patients are strongly encouraged to ask questions of their investigators and clinicians until they fully understand the risks.

Stem cells can theoretically improve the disease condition for as long as the modified stem cells remain life, potentially the entire lifetime of the patient.

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