Enzyme therapy for the lysosomal storage disorders: principles, patents, practice and prospects

Abstract

The lysosomal storage diseases (LSD) are a clinically heterogeneous group of inherited disorders associated with the accumulation of incompletely degraded macromolecules within membrane-bound bodies, usually as a consequence of a deficiency in the activity of a specific enzyme/hydrolase. Individual subtypes are characterised by a broad spectrum of disease manifestations, which reflect the cellular sites of substrate storage and resultant organ dysfunction. Until recently, most of the advances made in this field revolved around improved understanding of the biochemical and molecular basis of disease. With the introduction of enzyme therapy for Gaucher disease, proof of concept was established for this therapeutic approach in the management of LSDs. These developments have promoted a shift in the mindset of clinical investigators away from therapeutic nihilism and directed the focus of research from the bench to the bedside. These changes have also fostered collaborations between academia and industry, accelerating the pace of clinical investigations for additional single enzyme deficiency disorders potentially treatable by enzyme therapy. There are several patents for putative treatments of these rare disorders, and incentives to ensure the commercial success of these programmes have spurred the generation of a ‘cottage industry’ of biotechnology companies specialising in ‘orphan disorders’. This review will examine the scientific underpinning of the current therapeutic advances in the LSDs, describe the applications of enzyme therapy and delineate some of the major issues relating to long-term patient management. The evolving experience in this arena will be representative of patient-oriented research in the current era of molecular medicine, providing a paradigm for the emerging domain of the interventional geneticist. Future analysis of the return on investments made by venture capitalists for constrained markets in the healthcare sector should prove to be enlightening economics.

• enzyme therapy
• Fabry disease
• Gaucher disease
• GSD-II (Pompe disease)
• lysosomal storage disorder (LSD)
• MPS-I (HurlerScheie syndrome)