Targeted pharmacologic immunomodulation for inborn errors of immunity

Abstract

Inborn errors of immunity consist of over 400 known single gene disorders that may manifest with infection susceptibility, autoimmunity, autoinflammation, hypersensitivity and cancer predisposition. Most patients are treated symptomatically with immunoglobulin replacement, prophylactic antimicrobials or broad immunosuppression pertaining to their disease phenotype. Other than haematopoietic stem cell transplantation, the aforementioned treatments do little to alter disease morbidity or mortality. Further, many patients may not be transplant candidates. In this review, we describe monogenic disorders affecting leucocyte migration, disorders of immune synapse formation and dysregulation of immune cell signal transduction. We highlight the use of off-label small molecules and biologics mechanistically targeted to altered disease pathophysiology of such diseases.

Immunity and Genetics at the Revolving Doors of Diagnostics in Primary Immunodeficiencies

“…This is especially true for PIDs associated with Gain-of-Function pathways [ 14 ] that can be targeted by pharmacological inhibitors, which could be already available as developed to cure cancers [ 15 ]. The early detection of such “druggable” disorders is crucial to prevent the development of severe organ damage [ 16 ].…”

Addressing the challenges of novel therapies in rare diseases with mechanistic perspectives: Missed opportunities or the way forward?

“…This shows how seemingly unrelated conditions seem to benefit from novel therapies. The mTor pathway with the use of rapamycin has also been a successful approach for rare types of immune disorders 8 …”

“…The 2019 classification of Inborn Errors of Immunity by the International Union of Immunological Societies Expert Committee lists 430 inborn errors of immunity 7 . In their paper for this special issue, Sacco et al 8 discuss that while many of these patients are treated symptomatically with immunoglobulins, antimicrobials or immunosuppressants, these therapies do appear to modify the underlying disease and thus subsequent morbidity or mortality and may even affect the natural history of these disorders. Some promising results have been achieved with use of haematopoietic stem cell transplantation and gene therapy which offer potential therapeutic options in this wide spectrum of immune conditions.…”

“…In their review, Grech et al 12 describe how patients are finding hope through novel therapies such as haematopoietic stem‐cell transplantation, gene therapy, gene editing and base editing to address the underlying pathophysiology associated with this condition, which primarily include ineffective erythropoiesis, iron overload and globin chain imbalance. Interestingly jakinibs (also discussed by Sacco et al 8 ) were found to improve ineffective erythropoiesis and reversed splenomegaly in animal models of beta‐thalassaemia, however this did not translate into success in the subsequent human studies. Drugs that target transforming growth factor β (TGF‐β), such as luspatercept (ACE‐536), were also found improve erythroid maturation and red cell production and are now in clinical trial phase 13 …”

“…Unfortunately for most patients with rare diseases, treatment does not lead to a cure and the disease burden remains lifelong. However, the understanding of the dysregulation of a specific pathway can be extremely useful both prognostically and therapeutically 8 . Such mechanistic studies can lead to better and more robust models of disease and, eventually, successful approaches to treatment at a clinical level.…”