Interview: Inborn errors of immunity and the newer therapies becoming available

Before her arrival, Stefanski was an associate professor of pediatrics at the University of Minnesota and was actively involved in clinical care and research involving children with life-threatening blood and immune system disorders. One of her areas of focus was the use of cord blood units in stem cell transplants and other cellular therapy. She is board certified in both Pediatrics and Pediatric Hematology-Oncology.

In the last two decades, there has been a rapid evolution in the diagnosis and treatment of primary immunodeficiencies and the recognition of immune dysregulation, could you explain a) why this is and b) what point we are at currently with the diagnosis and treatment?​

We are more sophisticated with our molecular techniques of detecting genes in these disorders.  There are approximately 500 inborn errors of immunity causing genes and with the widely available sequencing methods this number continues to grow rapidly. Established treatment options currently consist of immune modulatory drugs, antimicrobial prophylaxis, immunoglobulin replacement therapy and, allogeneic hematopoietic stem cell transplantation (HSCT) as well as gene therapy.

Could you explain what causes inborn errors of immunity?​

Inborn errors of immunity (IEI) are caused by genetic mutations. They can be x-linked, autosomal dominant or autosomal recessive.  They can also be novel mutations that are not inherited. IEI present clinically as increased susceptibility to infections, autoimmunity, autoinflammatory diseases, allergy, bone marrow failure, and/or malignancy.

Until recently, management of treatment options were limited to prompt treatment of infections, gammaglobulin replacement and even bone marrow transplant depending on what was wrong. Could you outline the newer therapies including small molecule inhibitors, biologics, gene therapy etc?​

In all types of gene therapy for IEI, ex vivo​ gene therapy is used, in which a viral vector  is used to genetically modify cells from the patients with therapeutic intent. Gene editing can also be used where the DNA is repaired. Gene therapy has been used for multiple IEI including X-linked SCID, Artemis SCID, X-SCID, Wiskott-Aldrich Syndrome and Chronic Granulomatous Disease.

What difference have these made to the patients?​

These patients live longer, healthier lives and have a much better quality of life.  They are not hospitalized as frequently, they can attend school, they no longer need transfusions.  These therapies are life changing.

What efforts have been made to increase awareness of IEI?​

The advancement of genetic testing and diagnostic techniques have increased the awareness of IEI.  There are educational efforts to recruit young immunologists to the field as well as encouraging international collaborations. The development and widespread use of newborn screening have helped to identify severe combined immune deficiency (SCID) has also increased awareness.  These patients are identified immediately and have improved outcomes.  There are continual improvements and accessibility of genetic sequencing has accelerated identification of new IEI diseases. Advances and improvements in both gene therapy and hematopoietic stem cell transplant have made treatments possible in otherwise fatal diseases.

Could you explain ‘newborn screening’ and the advantages or any disadvantages this may have?​

Newborn screening identifies conditions that can affect a child’s long-term health or survival and is done within 24 hours after birth. Early detection, diagnosis, and intervention can prevent death or disability and enable children to reach their full potential.  The advantages are detecting life-threatening disorders early will impact that child’s health. Each year, new disorders, including IEI, can be detected on newborn screen.  The number of disorders detected varies by state.

Where would you like to see this field in terms of development within the next decade or two?​

A number of gene therapy trials using viral gene addition have been successful for ADA-SCID. Importantly, gene therapy approaches have become safer, more efficient and applicable to more IEI. Techniques for gene therapy continue to evolve and challenges include targeting the specific gene and minimizing the off-targets mutagenesis. The biggest obstacles remain cost and complex regulatory pieces.

Where is the industry at with inborn errors of immunity?​

We are continuing to improve gene therapy and expanding it to other IEIs.  We are making hematopoietic stem cell transplant safer for those that require transplant. The treatment for these disorders will change significantly in the next 10-20 years with more patients receiving gene therapy and additional IEIs being treated with gene therapy. We are truly on the cusp of novel therapies for these patients.