storage disorders (LSDs) are rare
heterogeneous inherited metabolic disorders that compromise over 50
distinguishable disorders. Each disorder results from defective function of a
specific lysosomal enzyme, leading to the accumulation of a wide range of
complex substrates including: glycosphingolipids, glycosaminoglycans, glycogen,
oligosachardies, cholesterol, peptides and glycoproteins. The accumulation of
these molecules in neurons progressively damages them, and eventually causes
their death (Parenti, 2015). Each disorder is characterized by specific
symptoms associated with the compromised enzyme, yet the age of onset and
severity of the manifestations vary among individuals with the same LSD.
Overall, this group of disorders significantly impact physical performance,
intellectual performance, quality of life, overall health, and life expectancy.
Although each disease is extremely rare, as a group they affect 1 in 8000-9000
live births (CITE).
Standard treatments include: enzyme replacement therapy
(ERT), gene therapy, substrate reduction therapy (SRT), and hematopoietic stem cell transplant (HSCT)
therapies. These therapies all aim to correct the defective enzymes, with the
desired effect of lowering the accumulated substrates. ERT is the most common
treatment. With this approach, the enzyme is delivered intravenously and is
then taken up by cells to reach lysosomes, where the enzyme then reduces the
levels of substrates within these cells. This infusion is typically 1-2 hours
and administered every 2 weeks (Parenti, 2015). Similar to this approach, gene
therapy aims to make up for enzyme deficiency through intravenous injection of
vectors containing a normal copy of the gene, where it is then taken up by
individual cells to create the functional enzyme. This approach has more
enduring effects than ERT, and the injections are less often. Contrary to these
approaches that increase enzymatic activity to help break down molecules,
substrate reduction therapy aims to reduce the amounts of substrates produce.
SRT consists of oral administration of