Hematopoietic Stem Cell Transplant for the Treatment of X-MAID

Abstract

We report outcomes after hematopoietic stem cell transplant for three patients with X-MAID, including 1 patient from the originally described cohort and two brothers with positive TREC newborn screening for SCID who were found to have a T-B-NK+ SCID phenotype attributable to X-linked moesin associated immunodeficiency (X-MAID). A c.511C>T variant in moesin was identified via exome sequencing in the older of these siblings in the setting of low lymphocyte counts and poor proliferative responses consistent with SCID. He received reduced intensity conditioning due to CMV, and was transplanted with a T-depleted haploidentical (maternal) donor. His post-transplant course was complicated by hemolytic anemia, neutropenia, and sepsis. He had poor engraftment, requiring a 2nd transplant. His younger brother presented with the same clinical phenotype and was treated with umbilical cord blood transplant following myeloablative conditioning, has engrafted and is doing well. The third case also presented with severe lymphopenia in infancy, received a matched related bone marrow transplant following myeloablative conditioning, has engrafted and is doing well. These cases represent a novel manifestation of non-radiosensitive X-linked form of T-B-NK+ SCID that is able to be detected by TREC based newborn screening and effectively treated with HCT.

A Murine Model of X-Linked Moesin-Associated Immunodeficiency (X-MAID) Reveals Defects in T Cell Homeostasis and Migration

“…A novel combined immunodeficiency disease termed X-MAID has recently been described in patients bearing a specific point mutation in the actin linker protein moesin (9)(10)(11)(12). To better understand the mechanistic basis of this disease, we generated CRISPR knock-in mice bearing the causative mutation (R171W, hereafter called X-MAID mice).…”

“…In addition, X-MAID/RagKO mice survived as long as their RagKO counterparts (data not shown). We therefore focused our analysis on the lymphoid compartment, giving special attention to T cells, where defects in X-MAID patients are observed (9)(10)(11)(12).…”

“…The importance of these processes is highlighted by the existence of several primary immunodeficiency diseases linked to mutations in actin regulatory proteins like WASp, WIPF1, Rac2, Hem1, and Dock2 (6)(7)(8). Recently, a new primary immunodeficiency disorder was described and attributed to mutations in the actin binding protein moesin (9)(10)(11)(12). Unlike other actin regulatory proteins linked to immunodeficiency, moesin does not regulate actin filament growth.…”

“…Recently, a dozen patients worldwide have been diagnosed with a novel combined immunodeficiency disease known as Xlinked moesin-associated immunodeficiency (X-MAID) (9)(10)(11)(12). Remarkably, eleven of the twelve patients have the same single point mutation within the moesin FERM domain (R171W).…”

Mini review: genome and transcriptome editing using CRISPR-cas systems for haematological malignancy gene therapy

“…In another study, REPAIRv2 transfected into HEK293T cells (CRL-11268 ATCC, Manassas, VA) consistently produced 20-40%, and up to 51% target-specific/desired edits without significant off-target activity in the transcriptome (Montiel-Gonzalez, Vallecillo-Viejo, and Rosenthal 2016). As such, CRISPR-Cas13 REPAIR may provide an efficient phenotype rescue alternative to haemopoietic stem cell transplant for immunodeficiency disorders caused by mutations in the Moesin (MSN) gene at c.511C [ T(p.Arg171Trp), rs1057519074 resulting in inhibited MSN protein production and primary immunodeficiency which is a known risk factor for haematology malignancy (Bradshaw et al 2018;Henrickson et al 2019;Lagresle-Peyrou et al 2016).…”