Hematopoietic Stem Cell Gene Editing as a Therapeutic Approach for IgA Nephropathy

IgA nephropathy (IgAN) is the most common form of chronic glomerulonephritis in Japan, yet no curative therapy is currently available. Accumulating evidence suggests that IgAN is driven by the production of abnormally glycosylated IgA and subsequent formation of pathogenic immune complexes. This raises the possibility that eliminating or correcting the source of aberrant IgA could achieve a true cure. Notably, reports of IgAN recurrence after kidney transplantation and remission following bone marrow transplantation point to a critical role of the hematopoietic system in disease pathogenesis. These findings led us to hypothesize that gene editing of hematopoietic stem cells (HSCs) eliminate the source of pathogenic IgA production could offer a fundamentally curative strategy for IgAN.

We first examined whether transplantation of HSCs from an IgAN-prone donor could transmit the disease phenotype to a non-IgAN recipient. HSCs were isolated and cultured from 7- to 10-week-old high-IgA (HIGA) mice and transplanted into age-matched C57BL/6 recipients. Donor chimerism was assessed monthly by flow cytometry. At six months post-transplantation, peripheral blood, kidney, and urine samples were collected for evaluation of serum IgA levels, glomerular IgA deposition, and urinary albumin excretion. Next, to determine whether disrupting IgA production in donor HSCs could attenuate disease activity, we performed CRISPR/Cas9-mediated gene editing to delete the IgA locus in HIGA-derived HSCs. These edited HSCs were transplanted into HIGA recipient mice, and renal tissues were analyzed four months after transplantation. Finally, to explore the translational potential, guide RNAs targeting the human IgA locus were designed and tested in CD34⁺ hematopoietic stem cells using CRISPR/Cas9.

Transplantation of HSCs from HIGA mice into C57BL/6 recipients resulted in progressive donor chimerism, increasing from 68.8% at 1 month to 98.2% at 4 months. All HIGA→C57BL/6 recipients exhibited mesangial IgA deposition (n = 4), whereas controls showed none (n = 5). Serum IgA and urinary albumin levels were significantly elevated in recipients of HIGA-derived HSCs compared with controls. Gene editing targeting the constant region of the Igha gene achieved an indel efficiency of 59.6% (n = 10) and markedly reduced the proportion of IgA-positive glomeruli (4.3% vs. 23.8% in non-edited controls). In human CD34⁺ HSCs, dual-guide RNA editing of the IgA locus achieved 98–100% efficiency, and transplantation into NOG-W41 mice is being conducted to validate engraftment and sustained editing in vivo.

This study demonstrates for the first time that transplantation of HSCs from IgAN-prone mice can transmit the disease phenotype, indicating that pathogenic alterations originate at the HSC level. Moreover, CRISPR/Cas9-mediated gene editing of HSCs effectively disrupted IgA production and reduced mesangial IgA deposition, providing proof of concept for a disease-modifying approach. Finally, successful IgA knockout and engraftment in human CD34⁺ HSCs highlight the translational potential of this approach, laying the foundation for future development of HSC-based, gene-edited curative therapies for IgAN.