June 8, 2017 One example of STAT1 GOF Mutation phenotype. Credit: Hiroshima University

Researchers report the first-ever study assessing how patients with "gain of function" mutation of the STAT1 gene respond to stem cell transplantation. It involved 15 young patients from nine different countries, each suffering a range of complications caused by the gene's mutation.

Of these, only six survived a regime of stem cell transplantationwith five completely cured and disease free by the study's conclusion.

The study was carried out by Dr. Satoshi Okada (Hiroshima University), Professor Jennifer Leiding (University of Florida), Professor Tomohiro Morio (Tokyo Medical and Dental University), and Professor Troy Torgerson (University of Washington).

Dr. Okada, who first discovered the STAT1 gain of function mutation in 2011, says, "Overall, this result is disappointing but the fact that five patients were cured proves that treatment with stem cells can work, and we now need to learn from these 15 individual cases."

The STAT1 gene plays a vital role in the body's immune system. Rare mutations can lead to STAT1's over-activation (GOF) and autoimmunity.

While the majority of patients afflicted typically show mild to moderate symptoms involving fungal (mostly Candida), bacterial, and viral infectionsabout 10 percent of cases are severe and life threatening.

Until now, developing suitable treatments has been challenging; e.g. anti-fungal drugs temporarily treat the symptoms but not the source mutation, and immunosuppressive therapies often do more harm than good by knocking out already overburdened immune systems.

With only one confirmed case prior to this study of a sufferer being successfully cured using stem cell transplantation, researchers are keen to build an understanding of best practices in order to offer real hope for the typically young sufferers of this condition.

The 15 selected patients were sourced via an international appeal to transplant centers and consortiums. Their ages ranged from 13 months to 33 years at the time of treatment. Screening by HU researchers confirmed that each had the STAT1-GOF mutation, and that the mutation was the source of their ailments.

Treatment was carried out independently by centers around the world. It used chemotherapy to eradicate the host's bone marrowthe source of the damaging STAT1 mutation in these patients. Healthy stem cell cultures sourced from donors were then transplanted into the subjects with the aim of reconstituting their bone marrow to a mutation-free, disease-fighting state.

The researchers suspect three reasons for the low 40 percent success rate:

In response, the researchers have made several proposals for improving this treatment. Due to most of the patients having mild to moderate ailments, only those suffering from severe symptoms should undergo this treatment. In addition, the chemotherapy dosage should be reduced. Those who received low-dose chemotherapy reacted better.

However, a balance must be struck. Low-dose chemotherapy may not eradicate host bone marrow to the extent required for its reconditioning the chance of transplant rejection is thus increased. With this in mind, support treatment may be required to neutralize host antibodies and prevent attacks of introduced stem cells.

Finally, due to the relative success seen in younger patients, stem cell transplantation should occur at as early an age as possible. Due to recent advancements in STAT1-GOF diagnosis, early detection is now a very real possibility hopefully leading to greater success rates, and less suffering for those carrying this potentially devastating mutation.

Explore further: 'Smart' genetic library makes disease diagnosis easier

More information: Jennifer W. Leiding et al. Hematopoietic stem cell transplantation in patients with Gain of Function STAT1 Mutation, Journal of Allergy and Clinical Immunology (2017). DOI: 10.1016/j.jaci.2017.03.049

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