Curing rare immunodeficiency diseases with gene editing

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We are working on editing defective genes with CRISPR, a method we hope can cure all primary immunodeficiency diseases in the future. The technique we are developing can also be used to treat cancer.

Primary immunodeficiency diseases are a collective term for several hundred different diagnoses. Around 600 people in Norway live with primary immunodeficiency diseases, which means that the bone marrow produces the wrong type of blood cells and immune cells.

Our group leader, Emma, says that there has been a lot of great developments in this area, but there are challenges with current treatment options. Our group is working on developing a method where we use gene editing, with the CRISPR technology, as a treatment for all primary immunodeficiency diseases.

I hope we can have a method for use in the clinic within five to seven years.

Infections, autoimmune diseases and cancer

Emma says that when she first started working with primary immunodeficiency diseases, they were considered very rare. You understood that patients had a terrible disease, but you didn’t understand what it was that they actually had. When the new gene sequencing technology came along, things changed, because it made it possible to sequence the entire DNA – the entire genome.

Suddenly, we received different diagnoses for these patients, and we were able to link them to different gene defects. We then realised that primary immunodeficiency diseases are not as rare as we had originally thought.

It had been thought that it was mainly about patients who got serious infections, but this new knowledge showed that the immune deficiency could have an effect in several different ways. Some have infections, but there are also patients with serious autoimmune diseases, and patients with a high fever who come and go, without an infectious agent being found. In addition, there are some patients who get rare forms of cancer.

The symptoms can be widespread, and patients often have to go through a number of different tests, sometimes over many years, before they receive the correct diagnosis. 

In recent years, newborns have been screened for severe combined immunodeficiency (SCID), and the screening catches two to three children per year. Most are caught without screening.

Current treatment has limitations

Regardless of whether the correct diagnosis is made, current treatment has its limitations. The sickest patients receive a bone marrow transplant. Other patients are given, among other things, preventative treatment with antibiotics and with immunoglobulins (antibodies).

There are also some new biological medicines, which are used for cancer and autoimmune diseases, which can be offered to immunodeficiency patients if their genetic defect is known.

Today, we know about 500 different genes that can have many different defects causing primary immunodeficiency diseases.

The problem is that for some of the patients these treatments only work for a period of time, and we don’t know why, or the patients only get a partial effect from the treatment. This can, for example, result in the patient’s autoimmune symptoms being controlled, but causing greater problems with infections.

This is the reason why Emma started to investigate whether CRISPR gene editing can be used to cure these diseases.

Correcting the patient's stem cells

The thinking is the same as in bone marrow transplantation, where the patient’s diseased bone marrow is replaced with healthy bone marrow cells from a donor.

With the CRISPR method we are working with now, we instead take stem cells from the patient’s own bone marrow and correct what’s wrong with them, before we put them back.

There are several advantages to CRISPR. Among other things, when you use bone marrow cells from a donor, there is a risk that these are rejected by the patient’s own cells. To prevent it, strong chemotherapy is necessary. In addition, it can be difficult to find a donor who matches the recipient. This applies, in particular, to the immigrant population.

With CRISPR, accessibility is not a challenge, and chemotherapy is not necessary.

The method has a major weakness

It may sound like a “simple” solution, but Emma emphasises that there are many obstacles still in the way.

CRISPR is currently very effective if you want to destroy part of the genome, such as simply cutting something out. But if you want to make a change, where you actually correct a mutation back to normal, it’s much more difficult.

We’ve worked hard on trying to do this in a safe and efficient way. So far, our group has worked with some disease models. But now we are taking a step further to reach the goal of being able to cure all primary immunodeficiency diseases. 

We’ve used some of the diseases as models, and what we are working on now is expanding so that we can use the technique on any patient, with any mutation, and correct it in the stem cells and put the cells back. The goal is for the method to be very effective and individually adapted.

The method has a major weakness, however. If the patient has modifications in a certain gene that increases the risk of cancer later in life, the CRISPR treatment can cause the cancer to break out earlier. Therefore, we won’t treat these patients. The risk is linked to a particular mutation (p53) and we have to screen the patients to look for such mutations.

It can also be used to treat cancer

Our group has become part of the new center for research excellence for personalised immunotherapy (PRIMA) at UiO. The reason why we are at a center which is mostly aimed at cancer is that the techniques we develop to treat primary immunodeficiency diseases can also be used to treat cancer.

When we treat immunodeficiency diseases, we correct mutations. When we treat cancer, we can insert corrective genes into T cells, so that those T cells can attack the cancer cells. It’s the same process.

Building up the infrastructure to provide cell therapy treatment in Norway

Today, when cell therapy treatment is used on patients in this country, the patient’s cells are sent abroad, where they are modified and then sent back. Our group works together with PRIMA and the newly established Center for Advanced Cell Therapy (ACT) to build up the infrastructure to be able to provide cell therapy treatment in Norway.

This is demanding treatment, so we must have a specific lab with people who know how to make the cell products we need, and clinicians who are used to such treatments. We’re in the process for building up this infrastructure so we can get such treatments out into the clinic.

Stem cell editing is being tested in the USA

The CRISPR method that we’re testing, with stem cell editing, is already in clinical trials as a cure for other diseases in the United States.

A method which is being tested and which has gone quite well, is treatment for sickle cell anemia and other diseases caused by defects in hemoglobin. Such hemoglobinopathies are quite easy to treat with CRISPR, and Emma believes this method will come to Norway within five years.

Whether we manage to deliver CRISPR treatment that can be used against primary immunodeficiency diseases within five to seven years depends, among other things, on how the clinical trials in the United States go. If they go well and there are no complications, it’s easier for us. If there are problems there, it may mean that it takes longer for us as well.

The biggest challenges include infrastructure and treatment price

We need infrastructure to scale up and produce these cells ourselves. The fact that it doesn’t exist and needs to be built up is the biggest challenge right now. There is some infrastructure, but it’s aimed at other types of cell therapy treatments. We’re now trying to make it bigger and more up-to-date.

The next big challenge will be that the price of this type of treatment will be high – especially at the start. This is often the case with new treatments, they’re expensive at the beginning, then the price goes down over time. But there may be a hurdle that will make it difficult to get the treatment into the clinics.

The alternative, bone marrow transplantation, costs significantly less when it goes well. When things go wrong, the treatment can still be very expensive. When a new method comes along, it really has to be much better for it to compete.

More opportunities to use CRISPR

There are also other ways to use CRISPR to treat this group of patients, for example by inserting CRISPR into the bloodstream, so that it corrects the stem cells inside the bone marrow by itself. But this is demanding and lies far in the future.

A third possibility is to correct the T cells – which are an important part of the immune system – instead of the stem cells.

This is simpler than correcting stem cells, but is only suitable for patients who have T-cell defects. It’s also uncertain how long such an approach will help.

Hoping to be able to treat rare cancers

In order to adapt the technique best for the Nordic patients, we work together with pediatric immunologist Hans Christian Erichsen Landsverk who works part-time in the project.

He is a senior physician and principally responsible for children and young people with immunodeficiency diseases at Oslo University Hospital (OUS). The vast majority of children and young people with immunodeficiency in Norway are treated there. Hans Christian contributes with clinical knowledge and recruitment of patients.

For the past six months, he has been working to find specific patient groups where it may be appropriate to use CRISPR to correct so-called peripheral T cells that should normally be activated against infectious agents.

When some of the immunocompromised patients get viral and fungal infections, it can be difficult for them to get rid of the infection. In some cases, it can be life-threatening. Being able to correct the peripheral T cells so that they could defend the patient against viruses and fungi would be fantastic.

One group of patients that has stood out are those who develop cancer because their immune systems are unable to control the Epstein-Barr virus, which usually causes kissing disease. The only way to treat this cancer in these patients is by bone marrow transplantation. 

There is a group of patients who are too old to have a bone marrow transplant. We rarely transplant after the age of 40 because the risk is too great.

If by changing the peripheral T cells with CRISPR, we could give their immune system better virus competence so that it recognises and can control the Epstein-Barr virus. We could stop the spread of cancer and get tumours to decline. It would save lives. These are rare conditions, but there are several patients in Norway who we will not be able to treat today if they develop cancer.

T cells will be the first step

He believes that correcting T cells will be the first step for clinical trials, while correcting the stem cells will come at a later stage. The consequences if things do not go as planned, will be greater with editing the stem cells. The risk is less when we work with peripheral T cells, because the T cells are usually only in circulation for a limited amount of time.

If, in the long term, it turns out to be safe and effective, we can also correct stem cells. Then it will be a final curative treatment on par with stem cell transplantation today.

Revolutionising the treatment for immunodeficiency

As of today, the relevant gene defects are known in around 30 percent of patients. And this is a prerequisite for being able to do gene editing. If we succeed in treating primary immunodeficiency diseases with CRISPR, it will to some extent revolutionise the treatment. Then we can correct exactly where the gene error is and hopefully manage with less chemotherapy as pre-treatment.

We now know about 500 different gene defects that cause immunodeficiency. Here, CRISPR can potentially be a huge advantage when we increase the efficiency of how many we manage to correct.

If we get an assembly line principle to correct gene errors, it’ll be a big step forward. Existing vector-based gene therapies for immunodeficiency have taken more than 10-15 years to develop for each of the diseases.

Hans Christian envisions that gene editing with CRISPR will become an important treatment for many monogenic diseases – that is, diseases that occur when a person has a defective gene – especially those that have to do with hematopoietic stem cells.

There are many people working with this all over the world. It’s going to be important. Whether it will happen in five, ten or fifteen years is difficult to say. The time perspective is difficult to imagine, because it is rare that everything goes as planned.

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