Less Is More: Substrate Reduction Therapy for Lysosomal Storage Disorders

Abstract

Lysosomal storage diseases (LSDs) are a group of rare, life-threatening genetic disorders, usually caused by a dysfunction in one of the many enzymes responsible for intralysosomal digestion. Even though no cure is available for any LSD, a few treatment strategies do exist. Traditionally, efforts have been mainly targeting the functional loss of the enzyme, by injection of a recombinant formulation, in a process called enzyme replacement therapy (ERT), with no impact on neuropathology. This ineffectiveness, together with its high cost and lifelong dependence is amongst the main reasons why additional therapeutic approaches are being (and have to be) investigated: chaperone therapy; gene enhancement; gene therapy; and, alternatively, substrate reduction therapy (SRT), whose aim is to prevent storage not by correcting the original enzymatic defect but, instead, by decreasing the levels of biosynthesis of the accumulating substrate(s). Here we review the concept of substrate reduction, highlighting the major breakthroughs in the field and discussing the future of SRT, not only as a monotherapy but also, especially, as complementary approach for LSDs.

Infantile gangliosidoses: Mapping a timeline of clinical changes

“…Miglustat works through inhibition of glucosylceramide synthase in the glycosphingolipid pathway [23]. For this reason, miglustat was thought to hold potential usefulness towards decreasing pathological accumulation of GM1 and GM2 gangliosides in the gangliosidosis diseases [12–14,24]. …”

“…The most common adverse effects of miglustat are gastrointestinal and include diarrhea, flatulence, and abdominal pain [15,21,24]. The gastrointestinal side effects are due to miglustat’s inhibition of the disaccharidase digestive enzymes in the gut, primarily maltase, sucrase, and to a lesser degree, lactase [15,21,24].…”

“…The gastrointestinal side effects are due to miglustat’s inhibition of the disaccharidase digestive enzymes in the gut, primarily maltase, sucrase, and to a lesser degree, lactase [15,21,24]. The disaccharidase inhibition can cause side effects of osmotic diarrhea when patients eat starchy foods and foods containing a high amount of carbohydrate [15].…”

Newborn Screening for Krabbe Disease and Other Lysosomal Storage Disorders: Broad Lessons Learned

“…Hence, other therapies are under evaluation [9,13,14]. These include gene enhancement, gene therapy [15], chaperone therapy, and substrate reduction therapy [16]. More recently, combination therapies, such as HSCT/ERT or HSCT/gene therapy, have been under investigation [13,14].…”

Nonsense Suppression as an Approach to Treat Lysosomal Storage Diseases

“…It is likely that this combination approach may also be required to treat LSDs, particularly in tissues such as the brain and the bone, which are resistant to current therapies. In order to restore a therapeutic level of protein function among recalcitrant tissues, nonsense suppression therapy and/or NMD inhibition may be viable options to complement other LSD treatment options, including: enzyme replacement therapy, the exogenous administration of purified recombinant enzyme [165]; substrate reduction therapy, which utilizes molecules that reduce the synthesis of the accumulation substrate [169]; and chaperone therapy, which uses compounds to stabilize misfolded, but functional, proteins [170]. With the continued development of more effective drugs, nonsense suppression therapy, alone or in combination with other therapeutic approaches, is likely to be a future treatment option for LSDs, as well as other genetic disorders, in patients who harbor nonsense mutations.…”