Low-dose Gene Therapy Reduces the Frequency of Enzyme Replacement Therapy in a Mouse Model of Lysosomal Storage Disease.

Marialuisa Alliegro,Rita Ferla,Carmine Settembre,Chiara De Leonibus,Alberto Auricchio,Edoardo Nusco

doi:10.1038/mt.2016.181

Abstract

Enzyme replacement therapy (ERT) is the standard of care for several lysosomal storage diseases (LSDs). ERT, however, requires multiple and costly administrations and has limited efficacy. We recently showed that a single high dose administration of adeno-associated viral vector serotype 8 (AAV2/8) is at least as effective as weekly ERT in a mouse model of mucopolysaccharidosis type VI (MPS VI). However, systemic administration of high doses of AAV might result in both cell-mediated immune responses and insertional mutagenesis. Here we evaluated whether the combination of low doses of AAV2/8 with a less frequent (monthly) than canonical (weekly) ERT schedule may be as effective as the single treatments at high doses or frequent regimen. A greater reduction of both urinary glycosaminoglycans, considered a sensitive biomarker of therapeutic efficacy, and storage in the myocardium and heart valves was observed in mice receiving the combined than the single therapies. Importantly, these levels of correction were similar to those we obtained in a previous study following either high doses of AAV2/8 or weekly ERT. Our data show that low-dose gene therapy can be used as a means to rarify ERT administration, thus reducing both the risks and costs associated with either therapies.

Highlights

Lysosomal storage diseases (LSDs) include more than 40 distinct inherited metabolic diseases as autosomal or X-linked recessive
Increased serum arylsulfatase B (ARSB) levels in mucopolysaccharidosis type VI (MPS VI) transgenic mice treated with combined monthly Enzyme replacement therapy (ERT) and gene therapy MPS VI mice received at postnatal day 30 (p30) a single i.v. administration of either 2 × 1011 or 6 × 1011 gc/kg of AAV2/8.TBG.hARSB, which encodes human ARSB under the control of the liver-specific thyroxine-binding globulin (TBG) promoter, and/or monthly i.v. injections of 1 mg/kg recombinant human ARSB (rhARSB) (Naglazyme, BioMarin Europe, London, UK), which is the dose currently used in MPS VI patients management.[6,7,49,50,51,52]
No significant differences in serum ARSB levels were observed in mice treated with combined gene therapy and monthly ERT compared with mice receiving only gene therapy (Table 1 and Figure 1)

Summary

Introduction

Lysosomal storage diseases (LSDs) include more than 40 distinct inherited metabolic diseases as autosomal or X-linked recessive. Extracellular phosphorylated or non-phosphorylated enzyme is taken up by the distal cells via either the mannose 6-phosphate receptors or the mannose receptor located on the plasma membrane, and trafficked to the lysosome.[2] This is the basis for cross-correction of deficient cells through enzyme replacement therapy (ERT), which is currently the standard of care for several LSDs.[3]. Despite its ability to ameliorate patient outcomes and slow disease progression, ERT has limited efficacy on some LSDs features, such as those related to bone, brain, cartilage, heart, and eye likely because of the poor biodistribution of recombinant enzymes through the bloodstream to these regions.[3,4] In addition, the requirement of weekly or biweekly intravenous (i.v.) infusions, which is due to the short plasma half-life of recombinant enzymes,[5,6] carries a risk of immune-mediated allergic reactions[7] and often requires a central venous access, resulting in a low quality of life for the patients. ERTs are extremely expensive and this represents a barrier for their widespread use in less developed countries.[4,8] there is high need to develop new therapeutic strategies with comparable or better efficacy than ERT, but without the inconvenience of multiple infusions associated to ERT

Methods

Results

Conclusion