Low dose gene therapy combined with rarified ERT offers hope for LSD patients

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TIGEM scientists demonstrate the therapeutic potential of a combinatorial gene therapy/enzyme replacement therapy (ERT) approach for lysosomal storage diseases (LSDs). Together, it reduces the risks and costs associated with gene therapy and ERT, respectively.

LSDs are a group of 40-50 rare monogenic disorders that result in disrupted lysosomal function and subsequent lysosomal pathology. ERT is the standard of care for several LSDs. However, ERT requires multiple (weekly) and costly administrations and has limited efficacy. High dose administration of adeno-associated viral vector serotype 8 (AAV2/8) has shown equal therapeutic efficacy as weekly ERT in a mouse model of mucopolysaccharidosis type VI (MPS VI), a rare LSD. But systemic administration of high doses of AAV bears the risk of cell-mediated immune responses and insertional mutagenesis. To overcome these issues, several studies have tested the therapeutic potential of combined therapies for the treatment of LSD in a safe and cost effective way.

The current study by Dr Alberto Auricchio and team at the Telethon Institute of Genetics and Medicine, Italy, investigated whether the combination of low doses of AAV2/8 with a less frequent (monthly) ERT schedule may be as effective as the single treatments at high doses and weekly regimen, respectively, for the treatment of LSD. The study was conducted in mice models of MPS VI, a rare LSD caused by deficiency of arylsulfatase B (ARSB), which leads to the lysosomal accumulation and urinary excretion of elevated amounts of the glycosaminoglycan (GAG) dermatan sulfate. MPS VI mice were treated with a single injection of the therapeutic AAV2/8 vector encoding ARSB vector at either 2 × 1011 or 6 × 1011 gc/kg and/or monthly injections of 1 mg/kg rhARSB protein. The treatment was started at postnatal day 30 and were followed up to 6-7 months of age.

Results showed that urinary GAGs decreased significantly more in mice receiving the combined therapy than in those receiving the corresponding single treatments implying an additive effect of the combination of gene therapy and ERT. Thus the study published in Molecular Therapy, provides preclinical evidence to show that low dose gene therapy can be used to rarify ERT administration, thus reducing both the risks and costs associated with either therapies.

Source: Low-dose Gene Therapy Reduces the Frequency of Enzyme Replacement Therapy in a Mouse Model of Lysosomal Storage Disease. Alliegro M et al., Molecular Therapy October 2016; DOI