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Blood to brain to the rescue
Richard L. Proia and Yun-Ping Wu
Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Address correspondence to: Richard L. Proia, Building 10, Room 9N-314, National Institutes of Health, 10 Center Drive MSC 1821, Bethesda, Maryland 20892-1821, USA. Phone: (301) 496-4391; Fax: (301) 496-9878; E-mail: proia@nih.gov.
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Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Address correspondence to: Richard L. Proia, Building 10, Room 9N-314, National Institutes of Health, 10 Center Drive MSC 1821, Bethesda, Maryland 20892-1821, USA. Phone: (301) 496-4391; Fax: (301) 496-9878; E-mail: proia@nih.gov.
Find articles by Wu, Y. in: PubMed | Google Scholar
Published April 15, 2004 - More info
J Clin Invest. 2004;113(8):1108–1110. https://doi.org/10.1172/JCI21476.
© 2004 The American Society for Clinical Investigation
Although individual lysosomal storage diseases are rare, as a group they represent a significant fraction of severe inherited metabolic conditions (1). The more than 40 different storage disorders cumulatively affect 1 in 5,000 live births. Most of the disorders are caused by the deficiency of a lysosomal enzyme activity that results in the progressive accumulation of the enzyme’s undegraded substrates. Since lysosomal enzymes are expressed ubiquitously, many organ systems are often affected. Generally, the pathophysiology of a particular disorder is related to the degree of substrate accumulation in a cell or tissue type — determined by substrate synthesis and degradation rates — and the sensitivity of the cell or tissue type to the stored substrate. A case in point is metachromatic leukodystrophy (MLD), which is caused by the absence of arylsulfatase A. A major substrate for the enzyme is galactosyl-3-sulfate ceramide (sulfatide), a component of myelin sheaths produced by oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system. In MLD, damage to oligodendrocytes and Schwann cells caused by storage of sulfatide results in demyelination, degeneration of the nervous system, and, in the most severe cases, death in childhood.
Neurodegeneration, a feature that MLD shares with the majority of lysosomal storage diseases, has made treatment of these diseases exceedingly difficult. Enzyme replacement therapies have been successful in preventing or reversing the somatic manifestations of some disorders by taking advantage of the cell’s efficient receptor-mediated uptake systems (2, 3). Lysosomal enzymes carry oligosaccharide structures that enable their recognition by plasma membrane receptors, which deliver the enzymes to lysosomes. Thus far, enzyme replacement therapy has proven unsuitable for treatment of the nervous system in storage diseases, because the blood-brain barrier precludes entry of proteins administered systemically. To circumvent this obstacle, strategies are being attempted that include direct introduction of gene transfer vectors or genetically modified cells into the nervous system (4–6). It is uncertain if such a highly invasive strategy would be suitable for the persistent and widespread correction needed for a globally affected nervous system found in many of the storage diseases. Another strategy utilizes small molecules that can pass through the blood-brain barrier to either partially inhibit substrate synthesis or stabilize the mutant enzyme (7, 8). While promising in concept, these approaches are in early stages.
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Nervous system damage-response pathway
The findings in this study (10) help clarify a damage-response mechanism relevant to the pathogenesis of lysosomal storage diseases and illustrate how it can be exploited for nervous system therapy (Figure 1). Microglia, resident macrophages of the brain, are continuously replenished by blood-borne precursors, which cross the blood-brain barrier and migrate into the parenchyma of the nervous system. They take up residence as resting microglia to surveil and defend the nervous system against damaging agents or conditions. When the nervous system is injured, as in MLD (10), a damage-response mechanism is activated that results in the enhanced recruitment of macrophages/microglia. Most significantly, there is preferential recruitment of macrophages/microglia to sites of substrate storage and pathology (10, 14). Thus, if the hematopoietic stem cells have been corrected for the lysosomal enzyme deficiency, the macrophages/microglia may be able to deliver enzyme directly to sites of damage.
Figure 1Damage-response pathway in lysosomal storage disease. Normally, nervous system microglia and macrophages can be derived from blood-borne precursors; they pass through the blood-brain barrier into the perivascular regions and ultimately take up residence in the parenchyma as resting ramified cells. When nervous system damage occurs, cytokines and chemokines are generated from activated macrophages/microglia and astrocytes, which can stimulate the up-regulation of adhesion molecules on nervous system endothelial cells, resulting in enhanced transendothelial migration of monocytes from the blood into perivascular regions. These enzyme-deficient cells migrate into the parenchyma to sites of damage where they may secrete potentially cytotoxic proinflammatory cytokines, leading to further damage and cell death. If the hematopoietic precursors are corrected, the macrophages and microglia gain the ability to transfer the missing lysosomal enzyme to deficient cells in the nervous system at sites of damage.
The vigorous process of recruiting macrophages/microglia into the nervous system and their subsequent activation may actually hasten neurodegeneration in lysosomal storage diseases. Studies utilizing a mouse model of Sandhoff disease, another sphingolipid storage disease exhibiting profound neurodegeneration, have shown that the population of activated macrophages/microglia expands considerably in the central nervous system prior to neuronal apoptosis (15). Intriguingly, the transplantation of these mice with bone marrow–containing hematopoietic stem cells substantially reduces macrophage/microglia activation and neuronal cell death without reducing substrate storage. Furthermore, blocking monocyte recruitment into the nervous system reduces neuronal cell death (Y.-P. Wu and R.L. Proia, unpublished data). These results indicate that the activated macrophages/microglia can trigger cell death possibly through the elaboration of cytotoxic, inflammatory mediators as has been suggested for other neurodegenerative conditions like Alzheimer disease.
The work by Biffi et al. (10) highlights the concept that therapeutic hematopoietic stem cell transplantation actually corrects a nervous system damage-response pathway defective in lysosomal storage disorders. Ex vivo genetic modification of hematopoietic stem cells to heighten expression of the missing enzyme in macrophages/microglia serves to restore and enhance the corrective potential of this pathway and to dampen its destructive capacity. Harnessed for therapy, the damage-response pathway appears unique in its capacity to afford widespread and persistent correction of a globally damaged nervous system as well as to target specifically affected areas. The approach taken by Biffi et al. (10), with its remarkable therapeutic effect on MLD, is particularly important because it outlines a strategy that may ultimately herald effective treatment of the nervous system in lysosomal storage diseases.
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