Non-myeloablative preconditioning with Ack-2 for cell therapy for Hunter disease

Mucopolysaccharidosis type II (MPSII; Hunter syndrome) is a lysosomal storage disorder caused by a deficiency in the enzyme iduronate 2-sulfatase (IDS). At present, the permanently therapeutic approaches for MPSII are bone marrow transplantation (BMT). And Hematopoietic stem cell (HSC)-targeted gene therapy (GT) might represent an alternative approach for overcoming the shortage of BMT. But these therapies have some limitations. In BMT, strong conditioning regimens, such as the use of a large dose of chemotherapeutic agent and irradiation, can sometimes cause severe side effects, such as infection and bleeding. And auto-HSC-based GT need preconditioning to make the space to settle down for transplanted-gene-modified-cell. Therefore, establishing milder conditioning regimens is very important. We studied the efficacy of administering a novel sequential treatment of parenteral ACK2, an antibody that blocks KIT, followed by low dose irradiation (LD-IR) for conditioning of BMT for wild-type and Hunter syndrome mice. This protocol did not make 100% but comparatively higher chimerism in white blood cells of peripheral blood of recipient mice. And this chimerism o remained the same level at 16 weeks after transplantation. GAG levels were significantly reduced in some organs of animals treated with this protocol. The extent of reduction in these mice was almost identical to that with 100% chimera, which indicates reconstitution with 100% donor cells is not required to obtain a therapeutic effect following bone marrow transplantation. Our findings suggest type ACK2-based preconditioning as a novel non-myeloabrative preconditioning for HSC transplantation for Hunter syndrome.