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Chapter 53 Lysosomal Storage Diseases: Perspectives and Principles 743

treatments have also been developed that are either aimed at slowing the half-life of the enzymes in the circulation was short lived, and (3)
the accumulation of undegraded materials (substrate reduction that the sugar moieties on the enzymes had an important influence
therapy [SRT]) or enhancement of the mutant protein function on their clearance from the circulation. In general, enzymes with
(chaperone therapy). terminal sialic acid residues had longer half-lives in the circulation
The majority of the clinical experience using cell-based therapy in than those with exposed mannose or M6P residues.
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LSDs comes from bone marrow transplantation (BMT). Bone Despite these early successes, the further development of ERT was
marrow has several advantages as a cell source, including the fact that limited by the inability of the academic-based research laboratories
it contains multiple stem and progenitor cell lineages that can lead to produce enough of the highly purified enzymes for long-term
to the repopulation of various organs and tissues. However, aggressive treatment studies. In addition, due to the very low numbers of
immunosuppressive preconditioning is required to achieve effective diagnosed patients at that time, there was little or no commercial
engraftment in the transplanted patients, leading to high morbidity interest in these diseases. In the 1980s, a small biotechnology
and, in some cases, mortality. In addition, graft-versus-host disease company (Genzyme, Cambridge, Massachusetts) took on this chal-
may occur. These deleterious effects can be severe and may lead to lenge and began to commercially prepare β-glucocerebrosidase, the
clinical complications in patients that are worse than the disorders enzyme deficient in Gaucher disease, from human placentas. This led
themselves. The availability of cord blood repositories and improved to the first long-term experience with ERT in patients with non-
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transplant methods has reduced these risks, but the possibility of high neurologic (type 1) Gaucher disease. Importantly, the purified
morbidity remains. enzyme was chemically modified to expose terminal mannose resi-
In LSD patients who have successfully undergone BMT and dues, leading to preferential uptake by macrophages, the primary
achieved a high level of engraftment, the clinical results have been cellular site of pathology in this disease.
variable. A number of factors account for this. First, repopulation The results of ERT in type 1 Gaucher disease were life changing
after BMT is not uniform throughout the body, and depending on and included remarkably reduced liver/spleen size and improved
the organ systems affected in the patients, clinical improvement may hematologic findings. Although the therapy required biweekly intra-
or may not occur. For example, the hematopoietic system is particu- venous infusions, it led to substantially improved quality of life and
larly amenable to BMT repopulation, but the skeletal system (cartilage was approved by the international regulatory authorities. Based on
and bone) is not. In the nervous system some transplanted bone this remarkable success, over a dozen companies are now involved in
marrow-derived cells may cross the blood–brain barrier and repopu- the development of ERTs and other therapies for LSDs. In addition,
late the CNS, but the number of these cells is small and the repopula- widespread efforts have been undertaken to diagnose patients, includ-
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tion efficiency low. A second factor accounting for the variable ing the recent implementation of newborn screening for these disor-
clinical results after BMT is the age at which the transplant is under- ders. These efforts have revealed that LSDs are more common than
taken. Many of the disease manifestations that occur in LSDs lead to originally thought, and it is estimated that they may occur in up to
permanent tissue damage (e.g., fibrosis, apoptosis) and are not revers- approximately 1 in 7000 live births, and could be even more enriched
ible. Thus, not only must efficient engraftment be achieved after in some regional, ethnic, and/or disease populations.
transplantation, but the procedure must also be undertaken before By the early 1990s, DNA technologies had evolved to the point
irreversible damage sets in, often in early childhood. where human recombinant β-glucocerebrosidase could be produced
Other than BMT, liver transplantation has been undertaken in in genetically engineered Chinese hamster ovary (CHO) cells, and
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several LSDs, also with variable success. Because the liver is a natural this eventually replaced the use of placental enzyme. Currently,
secretory organ, the concept underlying liver transplantation is that recombinant LSD enzymes are being produced in various sources,
even partial repopulation of this organ with healthy cells will lead to including CHO cells, transformed human cells, plants, and chicken
secretion of these proteins into the circulation and widespread meta- eggs.
bolic cross-correction. As with BMT, however, the uptake and distri- Based on the outstanding success in Gaucher disease, ERTs have
bution of the secreted enzymes will be limited by physiologic barriers now been developed for seven other LSDs, including Fabry disease
(e.g., the blood–brain barrier) and dependent on the vascular supply (α-galactosidase), Pompe disease (α-glucosidase), and several of the
to the tissue. Unlike BMT, there will no circulating stem cells avail- MPS disorders (MPS I, II, IV and VI). Several others are also under
able for organ engraftment other than in the liver. It is also of interest development. With these developments came the recognition that the
that early attempts at cell therapy for LSDs used amniotic cells for effects of ERT were disease specific and could be complicated by
transplantation. Although the engraftment of these cells was extremely immune reactions to the infused recombinant proteins. For example,
low and the clinical outcomes poor, these studies represented the first in contrast to the readily accessible hematopoietic system in Gaucher
embryonic stem cell-based approach for these disorders. disease, in other LSDs the major cellular targets for ERT (e.g.,
Simultaneous with the development of cell and organ transplanta- podocytes in the kidney, myocytes in the muscle, chondrocytes in the
tion for LSDs, investigators also began to isolate and study the cartilage) do not readily take up the intravenously delivered enzymes,
normal lysosomal proteins involved in the individual LSDs and to either because they do not express the proper cell surface receptors
explore the idea of protein (enzyme) replacement therapy (ERT). or do not have a sufficient vascular supply. In addition, the costs of
Because this work originated before the development of recombinant these therapies are extremely high, placing a very high burden on
DNA technology, it relied on discarded human materials as the reimbursement systems.
enzyme source, usually urine or placentas. “Proof-of-principle” for These realizations have led researchers to explore other therapies
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this approach was first documented by Neufeld and colleagues, who as well, work that has been greatly aided by the development of
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showed in an elegant series of studies that metabolic cross-correction animal models for most of the LSDs. Considerable early effort was
of MPS cells could be achieved by coculture of these cells with normal directed towards gene therapies, which have been extensively evalu-
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cells or by replacing the media in MPS cells with “conditioned” media ated in the animal model systems. Numerous clinical and pathologic
obtained from the normal cells. In addition, at around the same time improvements have been obtained, although the translation of these
methods of quantifying the levels or residual enzymatic activities in gene therapy technologies into the clinic has been slow because of
the LSDs were being developed, and there was also an early recogni- safety concerns and issues with large-scale vector production. Recently,
tion that very low levels of functional enzymatic activities in the the first gene therapy clinical trials for LSDs have been approved in
individual LSDs could have an important impact on the clinical Europe, and over the next decade the evaluation of this approach in
presentation of the individual patients. This suggested that low levels several of the individual diseases should be forthcoming.
of enzyme uptake were likely required to achieve metabolic cross- Other investigators have sought alternative therapeutic approaches
correction in vivo. for these diseases, focusing on inhibiting the production of substrate
The first short-term clinical experience with ERT took place in in order to reduce accumulation (SRT). For example, Miglustat
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the early 1970s by Brady, Desnick, and others. These early studies (OGT 918, N-butyl-deoxynojirimycin; trade name: Zavesca) is a
revealed (1) that the enzymes were generally well tolerated, (2) that low-molecular-weight compound that inhibits glucosylceramide