How close are we to therapies for Sanfilippo disease?

Metab Brain Dis (2018) 33:1–10 DOI 10.1007/s11011-017-0111-4 REVIEW ARTICLE How close are we to therapies for Sanfilippo disease? Lidia Gaffke 1 & Karolina Pierzynowska 1 & Ewa Piotrowska 1 & Grzegorz Węgrzyn 1 Received: 16 August 2017 / Accepted: 10 September 2017 / Published online: 18 September 2017 # The Author(s) 2017. This article is an open access publication Abstract Sanfilippo disease is one of mucopolysaccharidoses (MPS), a group of lysosomal storage diseases characterized by accumulation of partially degraded glycosaminoglycans (GAGs). It is classified as MPS type III, though it is caused by four different genetic defects, determining subtypes A, B, C and D. In each subtype of MPS III, the primary storage GAG is heparan sulfate (HS), but mutations leading to A, B, C, and D subtypes are located in genes coding for heparan N-sulfatase (the SGSH gene), α-N-acetylglucosaminidase (the NAGLU gene), acetyl-CoA:α-glucosaminide acetyltransferase (the HGSNAT gene), and N-acetylglucosamine-6-sulfatase (the GNS gene), respectively. Neurodegenerative changes in the central nervous system (CNS) are major problems in Sanfilippo disease. They cause severe cognitive disabilities and behavioral disturbances. This is the main reason of a current lack of therapeutic options for MPS III patients, while patients from some other MPS types (I, II, IVA, and VI) can be treated with enzyme replacement therapy or bone marrow or hematopoietic stem cell transplantations. Nevertheless, although no therapy is available for Sanfilippo disease now, recent years did bring important breakthroughs in this aspect, and clinical trials are being conducted with enzyme replacement therapy, gene therapy, and substrate reduction therapy. These recent achievements are summarized and discussed in this review. Lidia Gaffke and Karolina Pierzynowska contributed equally to this work. * Grzegorz Węgrzyn 1 Department of Molecular Biology, University of Gdańsk, Wita Stwosza 59, 80-308 Gdansk, Poland Keywords Sanfilippo disease . Neurodegeneration . Lysosomal storage . Enzyme replacement therapy . Gene therapy . Substrate reduction therapy Sanfilippo disease – brief description Mutations in 4 different genes cause mucopolysaccharidosis (MPS) type III, or Sanfilippo disease. These genes code for different enzymes participating in degradation of heparan sulfate (HS), one of glycosaminoglycans (GAG)s. Therefore, if mutations occur in both alleles of one of these genes (each subtype of Sanfilippo disease is inherited in autosomal recessive manner), HS accumulates in lysosomes which is the primary cause of the disease. Depending on dysfunction of particular genes and their products, 4 subtypes of Sanfilippo disease are distinguished, called MPS III A, B, C, and D (OMIM no. 252900, 252,920, 252,930 and 252,940, respectively). They result from mutations in SGSH (coding for heparan Nsulfatase), NAGLU (coding for α-N-acetylglucosaminidase), HGSNAT (coding for acetyl-CoA:α-glucosaminide acetyltransferase), and GNS (coding for N-acetylglucosamine-6-sulfatase), respectively. Patho-mechanisms and characteristic features of Sanfilippo disease have been reviewed recently, thus, these articles should be considered for more detailed information (Andrade et al. 2015; Fedele 2015; Jakobkiewicz-Banecka et al. 2016). Irrespective of the subtype, all persons suffering from Sanfilippo disease develop similar symptoms, though their severity and time of appearance may differ significantly from patient to patient. Unlike other MPS types, where extremely severe somatic symptoms develop, the major clinical problems of MPS III arise from cognitive defects and neurological dysfunctions (although they also occur in some other MPS types, it appears that central nervous 2 system (CNS) dysfunction is the most severe in Sanfilippo disease). The symptoms appear usually at the age of several month to a few years, and include developmental delay, cognitive decline, hyperactivity, sleep disturbances, aggression-like behavior, and seizures. At the late phase of the disease, hyperactivity and anxiety disappear, but patients lose their ability to move, and react poorly to external impulses. The life spam is usually between 2 and 3 decades (for detailed reviews see: Andrade et al. 2015; Fedele 2015; Jakobkiewicz-Banecka et al. 2016). Development of therapies for Sanfilippo disease Because the major clinical problems found in MPS III are due to CNS dysfunctions, development of effective therapy for Sanfilippo disease is extremely difficult. In some other MPS types (I, II, IVA, and VI), where severe somatic symptoms appear, enzyme replacement therapy (ERT) and, hematopoietic (or bone marrow) stem cell transplantation (HSCT) are available, which provide a possibility to manage various problems caused by the disease (Giugliani et al. 2016). However, even if appropriate enzyme is delivered to the blood of MPS III patients, it cannot cross efficiently the blood-brain-barrier, therefore, no significant therapeutic effects can be obtained. Despite the problems outlined above, in recent years, many excellent reports have been published which described a huge progress in the efforts to find a therapeutic solution for patients suffering from Sanfilippo disease. Three groups of potential therapies can be distinguished: modified ERT (in which the enzyme is either fused to a factor that is able to cross the blood-brain-barrier or administered directly to CNS), gene therapy, and therapies based on small molecules. Importantly, apart from studies on cellular and animal models of MPS III, clinical trials have been started with all these three therapeutic options. Although no such therapy has been registered yet, it may appear that we are quite close to obtain real therapeutic options for Sanfilippo patients in near future. In this review, the above mentioned works will be summarized and discussed, with special emphasis on possibilities of development of effective treatment procedures. We will focus on articles published during last 3 years, as previous works in this filed have already been reviewed (Andrade et al. 2015; Fedele 2015; Jakobkiewicz-Banecka et al. 2016; Sorrentino and Fraldi 2016), whereas this period was especially reach in breakthrough reports. It is worth to mention that due to specific clinical problems appearing in Sanfilippo disease (see above), it is very difficult to determine unambiguous tests which could be used in clinical trials for assessment of efficacy of tested therapies. This problem is enhanced by the fact that MPS III is a rare disease (prevalence is estimated between 0.3 and 4.1 cases per 100,000 newborns; Valstar et al. 2008), and Metab Brain Dis (2018) 33:1–10 thus, any clinical trial may involve only relatively small number of patients. Therefore, specific recommendations on clinical trial design for treatment of Sanfilippo disease have been recently established by a group of experts in the field (Ghosh et al. 2017). 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