AAV Gene Therapy Strategies for Lysosomal Storage Disorders with Central Nervous System Involvement - Gene Delivery and Therapy for Neurological Disorders - page 266

mucopolysaccharides (MPS), glycoproteins, and sphingolipids [ 1 ].
Cellular dysfunction and death result from different molecular
mechanisms such as direct toxicity of a substrate (e.g., psychosine in
Krabbe disease) or dysregulation of intracellular calcium homeo-
stasis (e.g., GM1-gangliosidosis) [ 2 , 3 ]. Most of the monogenic
LSDs are inherited in an autosomal recessive manner, though
notable exceptions include X-linked disorders such as Hunter syn-
drome (MPS II), Danon disease, and Fabry disease. There are at
least 50 LSDs, most often caused by a defi ciency or complete loss
of a soluble lysosomal enzyme [ 4 ]. Less commonly, LSDs may be
caused by defective accessory or lysosomal membrane proteins. For
example, the AB variant of GM2 gangliosidosis is due to the loss of
the GM2 activator protein, which is necessary for -hexosaminidase

to break down GM2 ganglioside [ 1 , 5 ]. Niemann-Pick disease type
C is caused by mutations in the NPC1 gene, which encodes a lyso-
somal membrane transporter. Dysfunction of the transport system
leads to storage of free cholesterol and other glycolipids in lyso-
somes [ 2 , 3 , 6 ].
Taken together, the incidence of all LSDs is estimated to be
1 in 8,000 live births [ 4 , 7 ]. Though infants and children are most
commonly and severely affected, late-onset forms of LSDs may
result from mutations that produce a less aggressive phenotype and
a spectrum of symptoms. Due to universal necessity of functional
lysosomes, LSDs present clinically with multiple organ pathology,
though severe neurological symptoms often overshadow periph-
eral disease manifestations [ 1 , 4 ]. Recent studies have now docu-
mented mild neurological disease in many LSDs once thought to
be non-neuropathic, such as Pompe disease [ 8 ].
The current standard of care for LSDs is ERT, in which patients
are regularly administered recombinant enzyme parenterally [ 9 ].
ERT is ineffective in treating the neurological components of
LSDs because of the blood-brain barrier (BBB). The structure and
physiology of the BBB prevent most high-molecular-weight sub-
stances, including proteins, from entering the CNS. Cell surface
receptors exist on brain endothelial cells to mediate transport of
macromolecules into the brain and thus play a fundamental role in
homeostasis of the CNS microenvironment. Unfortunately, no
such mechanism exists to transport circulating recombinant lysosomal
enzymes across the BBB even at high doses [ 10 , 11 ]. In order to
circumvent the BBB, many have successfully treated both small
and large LSD animal models by injecting recombinant lysosomal
enzymes directly into cerebrospinal fl uid (CSF) via intracisternal,
intrathecal, or intracerebroventricular (ICV) administration
[ 12 - 20 ]. Another approach that is currently the subject of intense
interest is to target lysosomal enzymes to the brain via fusion/
conjugation with protein domains/peptides derived from proteins
that are naturally transported across the BBB [ 21 - 27 ]. Additionally,
lentiviral-mediated ex vivo gene transfer of arylsulfatase A into a

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