Developing better therapies for rare immune diseases

Dr Emma Haapaniemi is head of the Precision Pediatrics and Gene Editing group at NCMM. Here, she describes the impacts and burden that rare immune diseases have on patients and how she is working to help provide them with a cure.

Dr Emma Haapaniemi. Photo: Matti Immonen

What are monogenic immune diseases, and what are the implications for those diagnosed with such a disease?

Monogenic immune diseases are genetic diseases of the immune system and are caused when a person has a defective gene in their DNA. This defect can lead to a susceptibility to certain types of infection or can result in overwhelming autoimmunity. People with these defects can also become very sick with allergies or even be predisposed to cancer. People with a genetic defect can also suffer from a combination of these complex conditions.  

There are around 300 known different genetic defects that, individually, are very rare but collectively they place a burden on the healthcare system. Generally, the patients require a lot of specialist care, which is difficult for them and their families. In terms of our group’s research, these patients are our target group. We work on developing CRISPR therapies to try to help treat them. 

How or when are such monogenic diseases typically diagnosed, and what is their prognosis?

There are certainly challenges when it comes to the diagnosis. Typically, these disorders are diagnosed using next-generation sequencing. However, often the diseases are so rare that doctors might not identify or suspect a genetic defect straight away. Patients can then go undiagnosed for a long time and become very ill as a result. Once a clinician suspects that there might be a genetic defect present, one in three patients will still not receive a correct diagnosis using the current methods. Either they have a disease that has not yet been discovered or the genetic disease is such that it is very hard to detect with the current diagnostics methods available. 

For a patient who is successfully diagnosed, there are treatment options. Many patients receive immunoglobulin replacement and antibiotic prophylaxis. The newer options are viral gene therapy and targeted immunotherapies originally developed for cancer and common autoimmune diseases. You can also try to completely cure the defect using a bone marrow transplant, however, this comes with challenges. Many of the patients tend to have quite advanced organ damage, such as lung, kidney, or skin damage, or they are suffering from inflammation throughout the body. It is then very difficult to conduct a bone marrow transplant due to the chemotherapy required. The new donor bone marrow cells also need to engraft into the patient’s bone marrow. If the patient is suffering from a lot of inflammation, this can be a difficult process.  

In Norway, all newborns are tested for a primary immune deficiency called Severe Combined Immunodeficiency (SICD) via the newborn screening programme. This process can also detect some other serious genetic disorders. If diseases are picked up at this early stage, usually a few days after birth, then a suitable treatment such as a bone marrow transplant can be done straight away. This results in a very good prognosis. However, if diseases are not picked up at such an early stage, the odds for a successful bone marrow transplant decline and thus the patients can become extremely sick or die. 

Can you describe how your research can help patients with a monogenic immune disease?

In our group, we focus on developing gene correction strategies for these diseases. One line of our research involves correcting mutations using stem cell therapies, whilst our other focus is to try and correct mutations by editing T cells.  

We hope that the stem cell correction approach could be used in the future instead of a bone marrow transplant. We also hope that T cell corrections could be used for patients who are so sick that they cannot go through a bone marrow transplant. With a T cell defect, you can collect these defective cells and correct them, which is a much less aggressive treatment. This would be used in the case of a patient who has severe infection or autoimmunity and treatment would likely be successful if they can receive their own corrected cells back.  

What challenges do you encounter with your research? 

There are certainly problems to overcome. In the case of stem cell transplants, such as stem cell gene editing, the process is not very efficient for most diseases, and there are also concerns that the edited cells could give rise to cancer. In diseases like sickle cell disease, however, stem cell editing has been efficient and the first human trials have been encouraging (

The second issue, when it comes to stem cell editing, is that for several of the diseases we study, we don’t have good animal models, which complicates some parts of clinical translation. In addition, the diseases are rare so we don’t have a huge group of patients to work with. For this to be a success, future clinical trials ideally need to be multi-centred and international. We’re not quite ready for this stage just yet, but are hopeful that this will happen in the future. 

T cell editing is more straightforward - there have been multiple clinical trials where T cells have been successfully engineered to treat cancer. However, in Norway, there are not so many corrected T cell editing pipelines and so they need to be established for us to progress with this.  

How do you work with clinicians in Oslo? 

Our group is now part of the GMP infrastructure development at Radiumhospitalet, Oslo University Hospital. The work is led by NCMM Associate Investigators Johanna Olweus and Karl-Johan Malmberg. Our group’s responsibility here is to set up the CRISPR genome editing in T cells, as well as to conduct the relevant toxicity studies. 

One of our main collaborators is Hans Cristian Erichsen, who is a pediatric immunologist at Oslo University Hospital. He has a cohort of STAT1 overactivation patients for whom he hopes he can use these T cell therapies. Patients with this rare mutation suffer from autoimmunity, where the body starts to attack its own healthy tissue. Most of these patients cannot undergo a bone marrow transplant, so we are now trying to set up our gene correction procedures for them. We have collected samples from them and together we are now designing correction strategies. Nail Fatkhutdinov, a postdoc in my group, is working hard on this. In addition, we work with Jochen Buchner who is a pediatric oncologist at Oslo University Hospital.  

What do you hope for the future when it comes to your research?

My ultimate goal is to push our work out into the clinic, and have the right pipelines and procedures up and running in the Nordics. Through my research, I would like to help patients with these rare diseases. Either by completely curing them or by significantly improving their quality of life. I think there is much that could also be done on the diagnostics side; when these patients are very young and diagnosed early it’s easier to provide them with the right care. However, once they cross into adulthood it becomes a lot harder to treat them, particularly if it’s not clear that they are suffering from a genetic disorder and they just continue to be very ill.  

Are there many others working in this field in Norway?

In diagnostics, Asbjørg Stray-Pedersen has worked hard to establish newborn screening and next-generation sequencing diagnostics for these diseases. In CRISPR editing, my group is quite pioneering. We have been lucky to be awarded large grants, which have helped us to move things forward and, despite our different research interests, we have been able to partner with other researchers locally. For example, Johanna Olweus is developing modified T cell receptors for cancer, which also involves setting up pipelines to expand and modify these cells in Norway. Even though we use CRISPR in our group, we can still use several of the same pipelines that she does.  

In addition, Karl-Johan Malmberg works on developing NK (natural killer) cell therapies for cancer. Despite his focus on cancer, many of the processes that he and my group use are the same and so we’re also able to collaborate here. In addition, we are part of a Centre of Excellence application for Cancer Immunotherapy (PRIMA, see ) which would involve working with seven other PIs. The application has reached the second stage and we’re positive that this will progress further. Outside of Norway, we collaborate with Rasmus Bak at Aarhus University. He is also trying to set up similar processes in the clinic in Denmark, so I also have some moral support here. 

Can you tell me what each of your group is focusing on now?

The group has grown nicely during the 2,5 years that I have worked at NCMM. Just to highlight some stand-out points from us; Ganna (Reint) and Zhuokun (Li) have worked very hard in identifying the CRISPR Cas9 polymerase fusion and we are working on patenting this. The project has resulted in a pre-print that is now up on BioRxiv (the preprint server) which is currently in review: “Rapid genome editing by CRISPR-Cas9-POLD3 fusion”  

Katariina (Mamia) has also done tremendous work in setting up the T cell editing protocols. Pavel (Kopčil) has also now successfully edited blood stem cells, including our first human blood stem cell transplant in a mouse model. In all these projects, we have trained or are training ~8 Erasmus or MSc students. Finally, Monika (Szymańska) has been a fantastic lab manager and a resource to both our group and NCMM. The group is in a great place now and, particularly after our funding successes, we’re looking forward to continuing to progress with our projects.


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