Hematopoietic Stem Cell Therapy and Novel Approaches for Mucopolysaccharidoses

Mini Review

J Blood Disord. 2014;1(2): 6.

Hematopoietic Stem Cell Therapy and Novel Approaches for Mucopolysaccharidoses

Edwards TN1 and Louboutin JP2*

1Faculty of Medical Sciences, University of the West Indies, Jamaical

2Department of Basic Medical Sciences, University of the West Indies, Jamaica

*Corresponding author: Louboutin JP, Department of Basic Medical Sciences, University of the West Indies, Mona Campus, Kingston, Jamaica.

Received: September 01, 2014; Accepted: September 22, 2014; Published: September 23, 2014


Mucopolysaccharidoses (MPS) are a group of inherited genetic linked enzyme deficiency lysosomal storage disorders. The deficiency of the enzymeis caused by a gene mutation that leads to the accumulation of harmful Glycosaminoglycans (GAGs) in the cells, tissues and blood. Disease-mutation leads to abnormal accumulation of GAGs: Dermatan Sulfate (DS), Heparan Sulfate (HS), chondroitin sulfate, and keratan sulfate resulting in clinical manifestations of varying severity. Recent advances have shown abnormal HS involvement in Central Nervous System (CNS) dysfunction. Therapeutic options vary according to the type of MPS. In severe MPS I patients, the best therapeutic approach is Hematopoietic Stem Cell Transplantation (HSCT). Unlike in other MPS, when it is performed in MPS I patients, HSCT has the ability to continuously produce the deficient enzyme that crosses the blood-brain barrier, a useful effect for CNS defects and in fine for mitigating cognitive and developmental delays. Pharmacological options include Enzyme Replacement Therapy (ERT). Three recombinant human enzymes have so far been approved by the US Food and Drug Administration (FDA) for the treatment of MPS: laronidase for MPS I, idursulfase for MPS II, and galsulfase for MPS VI. However, some of the results of ERT are still controversial. Finally, novel therapeutic avenues (i.e., substrate reduction therapy) have been recently proposed. We review here the different therapeutic approaches proposed in MPS, focusing on MPS I, the MPS that is benefiting most from HSCT so far.

Keywords: Mucopolysaccharidosis; Stem cell therapy; Bone marrow transplantation

Introduction and Epidemiology

Mucopolysaccharidoses (MPS) are a group of genetic-linkedmetabolic diseases that lead to significant morbidity and fatality in children and adults. MPS are a category of lysosomal storage disorder and comprises of seven clinical types (I, II, III, IV and VI, VII, IX) with specific gene mutations in eleven different lysosomal enzymes. The incidence of MPS has an estimate of 1:50,000 to 1:250,000 with MPSIII (Sanfillippo Syndrome), the most common and MPS VII (Sly disease) the rarest [1]. MPS are autosomal recessive with the exception for MPS II (Hunter Syndrome), which is X-linked. They are due to enzymatic deficit resulting in cellular damage with clinical features of varying degrees of severity [2,3]. In the case of MPS I patients, genetic mutations in the alpha-L-Iduronidase (IDUA) gene (located on chromosome 4p16.3) can be homozygous or heterozygous and are the causative mutation in 95% of cases [4]. According to the Human Gene Mutation Database, MPS I has 110 mutations in the IDUA gene with the majority of nonsense, missense mutations, splicing or small deletions/insertions [5,6]. In MPS I patients, there are more than 30 polymorphisms or nonpathogenic sequence variants within the iduronidase gene that modify the severity of the clinical disease presentation with a pathogenic allele [6,7]. MPS I alleles have variations among different ethnic populations with two nonsense mutations W402X and Q70X alleles found in majority of Europeans (61 to 72% mutations). The mutations found in the European population are rare among Japanese, Koreans, or Moroccan patients[6,8]. Specifically, in the Japanese population, there are two types of missense mutations that are conserved in patients displaying mild MPS I (Scheie) phenotype, while in India, other mutations are responsible for mild forms of MPS I [2]. Patients displaying the more severe phenotype of MPS I (Hurler), are usually homozygous for a nonsense allele or two different nonsense alleles, while milder MPS I forms (Hurler-Scheie and Scheie) have around 1 missense or null mutations [6,7]. Gene locations of other MPS are indicated in Table 1.

MPS are progressive in nature with clinical presentations of multisystemic, chronic and severe complications [3]. MPS features are presented in Table 1. For example, MPS I is separated into three different diseases based on their clinical presentation: Hurler (severe), Hurler-Scheie syndrome (intermediate) and Scheie syndrome (milder) [6]. According to their type, MPS I can be apparent in utero, in children or adults. MPS I am caused by the deficiency of lysosomal enzyme, IDUA, with subsequent improper degradation of Dermatan Sulfate (DS) and Heparan Sulfate (HS) [6]. The clinical manifestations of MPS I include progressive cardiac and pulmonary disease, inguinal and umbilical hernias, corneal clouding and musculoskeletal disease. Patients with MPS I (Hurler), the most severe phenotype, suffer from a progressive intellectual decline with CNS involvement, cognitive abnormalities and limited life expectancy [6]. Diagnoses are based on the accumulation of GAGs in the urine, a sensitive, but nonspecific, test. A more precise diagnosis involves the analysis of the deficient IDUA activity in the fibroblasts, leukocytes, serum or blood spots[6,9-11]. Prenatal screening is done through enzyme and DNA testing and early diagnosis such as newborn screening can improves disease outcome [6]. Diagnosis of MPS I patients are made between 4 and 18 months based on orthopedic and visceral signs. Births are usually normal but infants can present a giant mongoloid spot; cognitive dysfunction is the hallmark, but can be normal or slightly impaired according to the MPS I phenotypes [1]. Clinical manifestations and types of accumulated products of other MPS are featured in Table 1.

Citation: Edwards TN and Louboutin JP. Hematopoietic Stem Cell Therapy and Novel Approaches for Mucopolysaccharidoses. J Blood Disord. 2014;1(2): 1007. ISSN 2379-8009