Neuronal ceroid lipofuscinoses (NCLs) are rare, inherited lysosomal storage disorders, characterized by progressive mental retardation and motor developmental regression, and myoclonic seizures 1. Patients develop the disease early, almost in the childhood. Most patients have vision loss, and ultimately die in the early adulthood. The global incidence is 1.3–7.3/100,000 in live births 2. No epidemiological data in China is currently available and only 30 cases have been reporteduntil now 3. At present, the therapeutic approaches for NCLs are still mostly experimental and the disease is still considered as incurable. There are few reports on treatment of NCL for HSCT in the previous literature, and the case report has a poor effect after transplantation. However, some literatures reported that the treatment of NCL for HSCT can be tried. At the strong request of parents and approved by the ethics committee of the research center, this study conducted hematopoietic stem cell transplantation in NCL children. After the initial observation was effective, a series of follow-up treatments were carried out for children.
Previously, the NCLs were classified by the onset ages of patients: infantile NCL (INCL), late INCL, juvenile NCL and adult NCL 4. Patients were usually diagnosed according to the results of skin biopsy, blood enzymology and related protein tests. With the development of next-generation sequencing (NGS), mutations of different genes have been identified to cause NCLs. The NCLs are now classified according to the underlying gene defect. And the genetic analysis was used to help the diagnosis 5, 6. All NCL-related genes locate on autosomes, inheritances of which are autosomal recessive in most cases 7–9.
When neurological symptoms occur in patients, it is difficult to treat lysosomal storage disorders. Some previous experimental therapies, such as enzyme replacement therapy (ERT), have limited efficiency in improving the pathologies of the central nervous system. Other therapies, such as companion therapy, gene therapy, central nervous system ERT administration and cell therapy, have shown promising effects on the improvement of central nervous system. However, these methods are still in the experimental stage to a large extent. Hematopoietic stem cell transplantation (HSCT) has been suggested to be used in the treatment of lysosomal disorders and brain damage caused by a deficiency of soluble lysosomal enzymes 10. A probable mechanism of treating adrenoleukodystrophy through HSCT was proposed: the donor-derived monocytes penetrate the blood-brain barrier and differentiate into microglial cells, the enzyme deficiency is improved, and the progression of neuropathy could be stopped 11. Similarly, HSCT may be able to slow the progression of neuropathy in NCL patients. Allogeneic HSCT (allo-HSCT) from matched siblings is the primary treatment for benign diseases in children. However, most pediatric patients currently do not have a human leukocyte antigen (HLA) fully matched relatives or unrelated donors. Haploidentical parents can be served as alternative donors to provide biological factors to treat the disease. The major representative haploidentical transplantations include granulocyte colony-stimulating factors, anti-thymocyte globulin and post-transplantation high-dose cyclophosphamide. And a series of studies have shown the successful use of haploidentical donors in the treatment of hematologic malignancies and severe aplastic anemia 12–14. The failure of allo-HSCT limits its application in the treatment of benign diseases, especially the inherited metabolic disorders, the transplantation failure rate of which is higher than 20%15. Full donor chimerism may fail after the transplantations, and patients may develop graft-versus-host disease (GvHD). The haploidentical HSCT fails and the disease could not be cured. Thus, it is significant to prevent patients from GvHD after the haploidentical HSCT. Compared with the conventional T-cell depletion method, the post-transplant cyclophosphamide (PT/Cy) regimen used currently is safer, and induces fewer complications16. It enables rapid immune reconstitution in pediatric patients, expanding the pool of HSCT donors17. This method has been successfully used to treat some lysosomal storage diseases (such as Mucopolysaccharidosis18) with safety and efficiency. However, PT/Cy has not been reported to treat patients with NCLs previously.
In this study, we firstly performed allo-HSCT followed by the modified PT/Cy regimen on eight NCLs pediatric patients. All patients are still alive at present, and develop no severe transplantation-related complications. The progression of symptoms caused by the disease began to slow down at 12 months after the transplantation. Observations reported in this study suggest the potential to treat NCLs with haplo-HSCT and PT/Cy.