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Mucopolysaccharidosis type VII: A powerful experimental system and therapeutic challenge
Abstract:
Mucopolysaccharidosis type VII (MPSVII) is an inborn error of metabolism caused by a deficiency in the lysosomal enzyme B-glucuronidase (GUSB). As such, MPSVII is one of a larger class of inherited diseases referred to as lysosomal storage diseases (LSD). (1) The absence of GUSB activity leads to the progressive accumulation of undegraded glycosaminoglycans (GAGs) in many tissues of the body. Mucopolysaccharidosis VII has a complex clinical phenotype, including skeletal dysplasia, hepatosplenomegally, sensory deficits, cognitive impairment, and premature death. Although the natural history of the human disease is not precisely defined, small and large animal models of MPSVII have played a major role in our understanding of the disease process and towards effective treatments. The mouse model of MPSVII is a particularly powerful system due to its similarity to the human disease and the ability to generate large numbers of genetically defined animals. It has been shown in the murine model of MPSVII that recombinant enzyme replacement therapy (ERT) can ameliorate most of the clinical signs of disease if initiated during the neonatal period. Progenitor cell transplantation (hematopoietic, neuronal, mesenchymal) can correct many of the pathological signs of disease in MPSVII mice. Viral-mediated gene therapy has also been shown to decrease the severity of the disease in both the murine and canine models of MPSVII. Although pre-clinical experiments have shown that a number of approaches can effectively treat MPSVII, translation of those therapies into the clinic has lagged behind other LSDs. This is due in large part to the ultra-rare nature of MPSVII. Encouragingly, a clinical trial of ERT for MPSVII has recently been initiated. It will be interesting to determine if the positive pre-clinical data gathered in animal models of MPSVII translate to affected children. This clinical trial may also establish a paradigm for the treatment of other ultra-rare disorders.
Insights
Mucopolysaccharidosis type VII (MPSVII), a rare metabolic disorder, shows promise with enzyme replacement therapy (ERT) and gene therapy in animal models. Clinical trials are now underway to assess these treatments in humans.
Area of Science:
- Biochemistry
- Genetics
- Metabolic Disorders
Background:
- Mucopolysaccharidosis type VII (MPSVII) is a rare inherited metabolic disorder caused by a deficiency of the lysosomal enzyme B-glucuronidase (GUSB).
- GUSB deficiency leads to the accumulation of glycosaminoglycans (GAGs) in tissues, causing a severe, multi-systemic clinical phenotype.
- Animal models, particularly the mouse model, are crucial for understanding MPSVII pathogenesis and evaluating therapeutic strategies.
Purpose of the Study:
- To review the current understanding of MPSVII and its treatment landscape.
- To highlight the potential of various preclinical therapeutic approaches, including enzyme replacement therapy (ERT), progenitor cell transplantation, and gene therapy.
- To discuss the challenges and progress in translating these therapies to clinical application for MPSVII and other ultra-rare lysosomal storage diseases (LSDs).
Main Methods:
- Review of preclinical studies in MPSVII animal models (murine and canine).
- Analysis of therapeutic interventions such as recombinant enzyme replacement therapy (ERT), progenitor cell transplantation (hematopoietic, neuronal, mesenchymal), and viral-mediated gene therapy.
- Examination of the translation of preclinical findings to clinical trials.
Main Results:
- Preclinical studies demonstrate that ERT, initiated neonatally, can ameliorate most clinical signs in MPSVII mice.
- Progenitor cell transplantation and gene therapy have also shown efficacy in correcting pathological features in MPSVII animal models.
- Despite promising preclinical results, clinical translation for MPSVII has lagged due to its ultra-rare nature.
Conclusions:
- Therapeutic strategies like ERT, cell, and gene therapy show significant potential for treating MPSVII based on animal model data.
- A recently initiated clinical trial for ERT in MPSVII represents a critical step towards human treatment.
- Successful translation of these therapies could establish a paradigm for treating other ultra-rare LSDs.
