Gene therapy for lysosomal storage diseases: the lessons and promise of animal models

Abstract

There are more than 40 different forms of inherited lysosomal storage diseases (LSDs) known to occur in humans and the aggregate incidence has been estimated to approach 1 in 7000 live births. Most LSDs are associated with high morbidity and mortality and represent a significant burden on patients, their families, and health care providers. Except for symptomatic therapies, many LSDs remain untreatable, and gene therapy is among the only viable treatment options potentially available. Therapies for some LSDs do exist, or are under evaluation, including heterologous bone marrow transplantation (BMT), enzyme replacement therapy (ERT), and substrate reduction therapy (SRT), but these treatment options are associated with significant concerns, including high morbidity and mortality (BMT), limited positive outcomes (BMT), incomplete response to therapy (BMT, ERT, and SRT), life-long therapy (ERT, SRT), and cost (BMT, ERT, SRT). Gene therapy represents a potential alternative therapy, albeit a therapy with its own attendant concerns. Animal models of LSDs play a critical role in evaluating the efficacy and safety of therapy for many of these conditions. Naturally occurring animal homologs of LSDs have been described in the mouse, rat, dog, cat, guinea pig, emu, quail, goat, cattle, sheep, and pig. In this review we discuss those animal models that have been used in gene therapy experiments and those with promise for future evaluations.

Hematopoietic cell transplantation activity in Europe for inherited metabolic diseases: open issues and future directions

“…The most striking results have been reported in animal models of MPS VII and MLD. 8,9 The greatest hope currently centers on the use of injectable lentiviral vectors that are currently undergoing initial trials. However, it seems unlikely that these therapies will be available to patients within a few years.…”

Experimental rodent models of prostatitis: limitations and potential

“…45 Currently, many human noncancer diseases have appropriate animal models that serve as sources for obtaining new research data and testing new therapeutic strategies. [46][47][48][49][50][51][52][53][54][55][56] It should be noted that almost half the articles published on prostatitis and available on PubMed were published between the year 2000 and 2006. Nevertheless, the cause of category III and IV prostatitis has remained elusive.…”

Gem-diamine 1-N-iminosugars as versatile glycomimetics: synthesis, biological activity and therapeutic potential

“…74 The strategies for overcoming the deficit in enzyme capacity is to provide an endogenous supply of completely functional enzymes by direct infusion or by cellular replacement with cells capable of secreting enzymes (bone marrow replacement) or by gene delivery. [75][76][77] An alternative to enzyme replacement is to reduce substrate influx to the lysosome by inhibiting the synthesis of glycoconjugates. This strategy has been called substrate reduction therapy.…”