Why are some conditions more suitable for gene and cell therapies than others?

Depictions of gene and cell therapies in the news can make it seem like a ‘miracle cure’. Science fiction narratives often suggest that, in the future, they will be used to treat all illness and injury.

The idea of treating a condition or illness at its root may certainly seem more appealing than the idea of invasive surgery, or lifelong regimen of medication or physical therapy.

But to assess whether this is possible, or desirable, we need to consider: what makes a condition suitable for treatment by gene and cell therapies?

This explainer page is currently undergoing final review by members of the EuroGCT partnership.

Understanding the ‘root cause’ of a disease or condition

Gene and cell therapy work by correcting something which has gone wrong at a genetic or cellular level. This means that scientists need to understand what has gone wrong, and where it has gone wrong.

Understanding condition for treatment with gene therapy

The core principle of gene therapy is to replace a gene which is not functioning correctly with a healthy, functional gene (gene replacement therapy), or to alter the faulty gene so that it functions correctly (gene editing).

To identify the genetic cause of a condition, researchers must collect DNA samples from people living with that condition. The DNA is analysed and screened to determine the likely location of the genetic difference (mutation).

By comparing the results from different patients, scientists can identify the likely location of the mutation with greater accuracy. With enough participants, the specific gene mutation involved can be identified.

Understanding conditions for treatment with cell therapy

Cell therapy is used to treat conditions where a cell type, or tissue type, is not functioning as it should.

 Speaking very broadly, there are two reasons this happens:

the tissue has been damaged or destroyed by an injury or something outside the body (eg., burns, radiation), and needs to be replaced or restored. This requires an understanding of what purposes the healthy tissue serves, and what functions need to be restored.

The stem cells producing a cell or tissue type are faulty, and the mature cells they produce do not function normally (eg., leukaemia). This requires scientists to understand which stem cell population is producing the faulty cells, and what functions are lost, or disease state produced, as a result.

It can take a long time to find significant numbers of participants for rarer conditions

In order to confirm the genetic or cellular cause of a condition, scientists need to find a large number of individuals with the condition, invite them to participate in the screening study, and compare their screening results.

For rare conditions, it can take a long time to find enough people to take part, especially if a mutation occurs randomly (i.e. occurs in a sperm or egg cell, rather than being inherited from a parent parent with the condition).

If a rare condition is inherited (passed from one generation to the next), then researchers may study a particular family or community where multiple members are affected.

Not all conditions have a single 'root cause'

Many conditions cannot be traced to a single genetic or cell-based cause. Instead, they are the result of several genes, lifestyle factors, or both.

It is helpful to remember that while we speak about some conditions ‘running in families’, what this often means is a genetic predisposition. This means that a person’s combination of genes makes them more likely than average to develop a particular condition. This does not mean that they will definitely develop this condition, and it does not mean that people with an ‘average’ chance of getting a condition will never develop it. Lifestyle, behaviour, and luck all play a role.

Some conditions are more genetically complex than others

Conditions which are caused by a single gene (monogenic conditions) are attractive options for treatment by gene therapy. For example, sickle cell disease is caused by a single gene. This gene causes the protein to be shaped abnormally, which in turns causes abnormally shaped red blood cells. When successful, replacing this gene cures the condition.

Many conditions are not controlled by a single gene. These conditions (polygenic conditions) are the result of the interaction of several different genes. In some cases, the genes associated with a condition have not been identified with certainty – only correlates. In this case, gene therapy to treat the ‘root cause’ is not possible.

Even if scientists could identify every gene involved in a particular condition, it would be unwise to try to alter all of them. Many genes are enmeshed in other networks, and changing them would have complicated knock-on effects.

Recreating tissues for transplant

The idea of treating tissue that is not functioning correctly, or which has been severely damaged, with a ‘lab-grown’ replacement is appealing. However, the difficulty of this task depends on the region of the body affected.

Some conditions can be treated by destroying the patient’s own stem cells, which are producing faulty cells, and replacing them with healthy stem cells from a donor. These healthy stem cells divide and differentiate in the body, producing new, healthy tissue within the patient. These stem cell transplants can be used to ‘regrow’ complex networks of multiple cell types. One of the best-known examples is bone marrow stem cell (blood stem cell) transplants.

Delivering and integrating therapies into the body

Gene and cell therapies need to be delivered to the right area of the body and activated at the right time, for the right length of time. This need for precision presents many challenges.

Different tissue types require different ways of delivering a therapy

Some tissues are easier to access to treat than others. For example, blood cells can be delivered as an infusion. They are then transported around the body by the body's own circulatory system.

For solid tissues, the delivery needs to be more precise. If a gene therapy is delivered to the wrong tissue, or the wrong part of a tissue, and a gene is activated in the wrong part of the body, this can lead to serious consequences such as tumour growth.

Not all tissue types have the same capacity to support new tissue growth

Some gene and cell therapies aim to correct repair to a damaged tissue. Many of these rely on tissue engineering techniques.

Risk and benefit

Any new therapy comes with unknowns, risks, and costs. With limited funding, and limited researchers to investigate different avenues, funders and researchers must consider where their efforts are most likely to be successful. Researchers and funders have to consider several questions.

Is a therapy likely to be possible? Does the basic science suggest that gene and cell therapy would work for this condition? As discussed above, gene and cell therapy is less likely to work as a solution for conditions which have several inter-linking causes.
Would we need to develop new technologies to investigate the question? Are the laboratory and clinical techniques already in place? Are there research teams which could start investigating this question right away if they had enough time and funding?
Would a new therapy meet an unmet need? Even if a gene and cell therapy could be developed, it might not be the right therapeutic solution. Is there an existing traditional therapy? Are people living with this condition satisfied with this therapy? Are the risks and side-effects of this therapy considered acceptable? (This is a complicated question - just because a therapy is considered safe for the market does at the benefits are worth the risks and side-effects.) Gene and cell therapies carry their own risks and complications, and developing new therapies is costly. If there is an existing therapy with a high success rate, researchers and funders may decide to prioritise research on conditions which cannot currently be treated effectively.

Where does this leave us?

As with all therapies, there are challenges in developing gene and cell therapies. These challenges may be biological, technical, or logistical. Some may be overcome as researchers progresses; others will take political effort.

It is important to remember that for all the promise of gene and cell therapies, they are not the gold standard for all conditions. Traditional therapies can greatly improve the quality of life for people living with hard-to-treat conditions. For some conditions and some individuals, they may present a more suitable solution than gene and cell therapies. Gene and cell therapies are one tool among many for treating congenital and difficult-to-treat conditions.

What conditions can currently be treated using gene and cell therapy?

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