Assessment of hematopoietic and neurologic pathophysiology of Hax1 deficiency in a Hax1-ko mouse model.

Severe Congenital Neutropenias are a heterogeneous group of genetic disorders of the hematopoietic system and are characterized by low neutrophil counts. Kostmann syndrome, which is caused by HAX1 deficiency, is the most common form of autosomal recessive inheritance. All affected children present with severe granulocytopenia and consequently life-threatening bacterial infections since birth. The granulocytopenia can be treated with life-long administration of Granulocyte-Colony Stimulating Factor. About 10% of patients affected by HAX1-deficiency suffer from severe and untreatable neuropsychological impairment, whose molecular pathophysiology is not fully understood. To shed more light on this, we have studied the hematopoietic and nervous systems of a Hax1-knockout mouse model. We found that the murine Hax1-deficient hematopoietic system is characterized by slightly decreased hematopoietic stem and progenitor cell numbers and a reduced spleen B cell pool. In the nervous system, we observed that neurons of the striatum suffer from a very severe post-natal apoptotic process leading to a Parkinson-like motor impairment, which is lethal within 8 weeks after birth. As a potential therapeutic tool for stable genetic modification of hematopoietic stem cells, we developed an HAX1-expressing self-inactivating lentiviral vector and tested in-vivo ectopic vector-driven HAX1 expression in wild-type hematopoietic cells after transplantation without revealing any clear histo-pathological signs of hematological malignancies. Our studies expand the understanding of the molecular and cellular pathophysiology of the hematopoietic and neurological systems in a murine model of Hax1 deficiency and, although the Hax1-ko mouse model does not present with neutropenia, provide important information to guide future developments of gene therapy-based treatment of Kostmann syndrome.