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Introduction of Mucopolysaccharidoses

Mucopolysaccharidoses (MPS) are a group of inherited metabolic disorders caused by the accumulation of complex carbohydrates, known as glycosaminoglycans (GAGs), throughout the body. The development of these diseases is due to the deficiency of specific lysosomal enzymes responsible for the degradation of these complex carbohydrates. Depending on the type or severity of MPS, it can lead to various clinical symptoms, such as coarse face, hearing loss, CNS impairment, respiratory compromise, hepatosplenomegaly, heart valve disease, skeletal dysplasia, and gait abnormalities.

While there are some traditional treatments available for MPS, such as enzyme replacement therapy (ERT), substrate reduction therapy (SRT), and hematopoietic stem cell transplantation (HSCT), these therapies are often limited in their ability to address the underlying genetic defect. In recent years, genetic therapy has emerged as a one-time permanent therapy, repairing enzyme deficiencies.

Application of Gene Therapy in Mucopolysaccharidoses

Gene therapy involves modifying genetic information within a cell (through gene replacement or gene editing) to treat a disease. By addressing the underlying cause of the disease, this approach has the potential to provide a lasting cure for MPS. Several different gene therapy approaches for MPS are being explored, including AAV-mediated gene therapy, hematopoietic stem cell (HSC) gene therapy, and genome editing technologies.

Fig. 1 In vivo and ex vivo gene therapy approaches for MPS.Fig. 1 In vivo and ex vivo gene therapy approaches for MPS. (de Castro M J, et al., 2021)

Viral vectors such as adenovirus (AdV), adeno-associated virus (AAV), and lentivirus (LV) are currently the most commonly used methods for introducing genes into cells for gene therapy. Non-viral gene delivery has been tested in MPSI and MPSVII mouse models but with limited success. Current studies focus on AAV and LV vectors for the replacement of relevant transgenes.

Transplantation of gene-modified HSCs is another promising therapeutic approach for MPS, involving the reintroduction of relevant corrected genes into HSCs and their subsequent transplantation into patients after chemotherapy. LV vectors are particularly popular among ex vitro stem cell gene therapy approaches because of their ability to stably integrate genomes into transduced cells. Once integrated, the lentiviral genome propagates throughout subsequent generations.

Genome editing technologies such as CRISPR/Cas9 are also being explored as potential gene therapy approaches for MPS. These technologies involve direct editing of the patient's genome to correct the underlying genetic defect responsible for the disease. Delivery of gene editing machinery requires a vector, typically AAV, to deliver the components. Most gene editing studies for MPS focus on MPSI using both viral and non-viral delivery methods.

Current Gene Therapy Clinical Trials in Mucopolysaccharidoses

There are currently several ongoing clinical trials exploring gene therapy for MPS. One example is Abeona's next-generation AAV-based gene therapy for MPS III (Sanfilippo syndrome). Their approach involves using AAV vectors to deliver a normal copy of the defective gene to central nervous system cells, with the aim of reversing genetic errors. The company has enrolled its first MPS III B patient in a Phase 1/2 clinical trial for their ABO-101 (AAV-NAGLU) gene therapy, which is designed as a single treatment approach.

Regenxbio has developed two gene therapies for MPS, including RGX-111 for MPS I and RGX-121 for MPS II (Hunter syndrome), which are designed to deliver the human α-l-iduronidase (IDUA) gene and iduronate-2-sulfatase (IDS) gene to the CNS, respectively, using AAV9 vectors. Regenxbio has announced the completion of the RGX-111 phase I/II trial for severe MPS I and is recruiting patients to participate in the RGX-121 phase I/II/III CAMPSIITE™ trial.

Lysogene is developing a gene therapy candidate LYS-SAF302 for MPS IIIA, which involves directly delivering the human SGSH gene to the central nervous system using the AAVrh10 vector. Lysogene's Phase 2/3 clinical trial for MPS IIIA is ongoing. This treatment has been granted Fast Track, Rare Pediatric Disease, and Orphan Drug Designation in the US, and Orphan Drug Product Designation in the EU.

In addition to these clinical trials, there are other phase I/II clinical trials for MPS I, MPS II, MPS IIIA, MPS IIIB, and MPS VI that are in progress or planned. Furthermore, the fact that in vivo genome editing therapy of MPS has been carried out for the first time in humans is very promising.

While there are still challenges to be addressed, such as the need for efficient delivery systems and the potential for immune rejection, current clinical trials and preclinical studies are showing promising results and offer hope for the development of a long-lasting cure for MPS.


  • de Castro, M. J.; et al. Gene therapy for neuronopathic mucopolysaccharidoses: state of the art. International Journal of Molecular Sciences, 2021, 22(17): 9200.

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