Emerging therapies and therapeutic concepts for lysosomal storage diseases

Abstract

Introduction: The success of the first enzyme replacement therapy (ERT) for a lysosomal storage disease (LSD) and the regulatory and commercial incentives provided by authorities for orphan and rare diseases has spawned a massive interest for developing drugs for these intriguing but devastating genetic disorders. The potential for new drugs in this arena is vast, as not only a high number of LSDs have no available therapy, but also alternative therapeutic approaches for diseases with existing treatment are much needed as a number of challenges facing the existing therapies have become very obvious. A significant unmet medical need is therefore apparent for most, if not all of the LSDs and the development of new therapies based on the increasing knowledge of the pathophysiological mechanisms involved in these devastating diseases is therefore anticipated with great interest from all stakeholders.

Areas covered: The reader will be introduced to the intricate biological processes involved in lysosomal regulation and how these are exploited for current and emerging therapies. Therapies utilizing these processes will be thoroughly reviewed with regard to their mechanism of action, their clinical status and the challenges they are faced with and/or are aiming to address. For this review, a literature research has been undertaken that covers the years 1955 – 2012.

Expert opinion: The interest in lysosomal biology and disease has surged over the past decade not only in the halls of science but also of pharmaceutical companies. As the complexity of the LSDs increasingly become revealed, so do novel therapeutic targets continuously nurturing the development of new candidate drugs for these devastating diseases. Among this multitude of approaches, the ERTs still account for the vast majority of approved therapies but a number of exciting alternative approaches are emerging targeting various components of the pathophysiological cascade. This evolution of the field is much needed as the presently available treatments are unable to address all clinical aspects of these multifaceted diseases. Future therapy will most likely consist of combinations of these established and emerging approaches as well as other yet to be discovered concepts as the complexity of the diseases demands a certain degree of humbleness to the expectations for a cure based on a single therapy.

Keywords::

• chaperone
• enzyme replacement
• Fabry disease
• Gaucher disease
• glycosphingolipids
• lysosomal storage disease
• lysosomes
• substrate optimization
• substrate reduction
• therapy

Declaration of interest

The author is employed by and holds shares in Orphazyme ApS, which develops therapies for lysosomal storage diseases.

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