A First-in-Human Base Edit Gene Therapy for CD40L Deficiency X-Linked Hyper IgM (XHIGM) Syndrome

CD40L-deficient X-linked hyper IgM (XHIGM) syndrome is characterized by defective B cell class switching, deficiency of immunoglobulins G, A, and E, plus other immune abnormalities due to disrupted CD40L–CD40 interaction. Allogeneic hematopoietic stem cell (HSC) transplant can cure XHIGM but requires myeloablative conditioning and risks graft versus host disease (GVHD), posing a high mortality risk. We developed ex vivo base editing (BE) of autologous HSC and T cells to treat a 37-year-old man (P1) diagnosed late in life with a CD40LG c.C>T p.Q220X mutation in a single-patient Investigational New Drug application targeting his mutation (IND32000; NIH protocol 002385). Preclinical studies achieved >90% gene correction of P1 HSC and T cells with base editor ABE8e SpWT/A5 guide, devoid of significant unintended off-target edits. BE-HSC was intended as a definitive transplant to achieve long-term hematopoietic and immune reconstitution, whereas the BE-T cells were designed to serve as a transient bridge therapy of functional T cells during the period preceding differentiation of T cells from the BE-HSC graft. P1 presented pre-gene therapy with sclerosing cholangitis, cryptosporidium infection, nodular regenerative hyperplasia, portal hypertension, bronchiectasis, and lacked HLA-matched donors. Autologous BE-HSC transplant was given after low-dose busulfan conditioning together with prophylactic defibrotide to mitigate chemo-related veno-occlusive disease. The original treatment schema was alemtuzumab (days −21, −20, −19), busulfan 6mg/kg total (days −3, −2) with prophylactic defibrotide, BE-HSC (day 0), and BE-T on day +14 and as indicated for lymphopenia and/or infection. Following alemtuzumab, P1’s baseline abnormal liver function tests (LFTs) worsened (transaminases approximately doubled, bilirubin increased ∼18-fold) with persistent detection of previously undetectable cryptosporidium. We paused busulfan and BE-HSC and administered BE-T products, which corrected LFTs sufficiently to allow uneventful busulfan conditioning and BE-HSC product infusion. Post-treatment at months 1 and 2, blood studies confirmed robust engraftment with normal wild-type alleles in myeloid cells (>90%) and increasing levels in natural killer (>60%), B (>40%), and T (27%) cells and with first-time detection of class-switched IgG+ B cells. This innovative, dual-product strategy provides immediate, on-demand immune protection through infusion of functional BE-T cells, effectively bridging patients through the critical pre-engraftment period and until BE-HSC achieves durable, multilineage reconstitution.