Supply-Side and Trickle-Down Therapy
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Supply-side and trickle-down therapy Gregory A. Grabowski J Clin Invest. 1999;103(4):439-440. https://doi.org/10.1172/JCI6290. Commentary The glycosphingolipid (GSL) storage diseases have occupied a position of importance in biochemistry, intermediary metabolism, genetics, and gene product therapy disproportionate to their frequency in the population. In this issue of the JCI, Liu et al. (1) extend this history by providing “proof-of-principle” for potential new therapies of lysosomal storage diseases (LSDs) and raise general issues relevant to phenotypic expression. In essence, Liu et al. show that “nonessential” metabolic intermediates — selected GSLs with singular major synthetic and degradative pathways — can be eliminated and thereby decrease storage without apparent adverse effects. Although genetically based, Liu et al.'s approach is conceptually identical to the successful dietary restriction therapies for amino/organic acid disorders and to the inhibitor therapies for dyslipidemias. With a few notable exceptions, GSL storage diseases result from single gene– single enzyme defects, and the consequent accumulation of hallmark substrates for specific phenotypes. Radin (2) suggested that the phenotypes developed from substrate flux disruptions that in turn depend on the inflow and outflow rates of intermediates, and directed attention to the supply side (Fig. 1). If either rate is altered beyond a threshold level, intermediates will accumulate and produce phenotypes. This threshold model (3) implies that the flux through the metabolic pathway can be altered by increasing the amount of residual enzyme (increase the trickle) or by decreasing the substrate […] Find the latest version: https://jci.me/6290/pdf Supply-side and trickle-down therapy Commentary See related article Gregory A. Grabowski this issue, pages 497–505 Children’s Hospital Research Foundation, Division of Human Genetics, Cincinnati, Ohio 45229-3039, USA Address correspondence to: Gregory A. Grabowski, Children’s Hospital Research Foundation, Division of Human Genetics, 3333 Burnet Avenue, Cincinnati, Ohio 45229-3039, USA. Phone: (513) 636-7290; Fax: (513) 636-2261; E-mail: [email protected] The glycosphingolipid (GSL) storage gene–single enzyme defects, and the cies of β-hexosaminidases A and B (β3) diseases have occupied a position of consequent accumulation of hallmark and the “Sandhoff phenotypes” with importance in biochemistry, intermedi- substrates for specific phenotypes. CNS GM2 ganglioside and visceral globo- ary metabolism, genetics, and gene Radin (2) suggested that the pheno- side storage (5). The CNS phenotypes product therapy disproportionate to types developed from substrate flux dis- result from the cellular effects, albeit their frequency in the population. In this ruptions that in turn depend on the poorly characterized, of the accumu- issue of the JCI, Liu et al. (1) extend this inflow and outflow rates of intermedi- lated GM2 ganglioside. Sandhoff mice history by providing “proof-of-princi- ates, and directed attention to the sup- have progressive motor behavior loss ple” for potential new therapies of ply side (Fig. 1). If either rate is altered and shortened life span (6). Liu et al. lysosomal storage diseases (LSDs) and beyond a threshold level, intermediates substantially, but not completely, obvi- raise general issues relevant to pheno- will accumulate and produce pheno- ated this Sandhoff phenotype by typic expression. In essence, Liu et al. types. This threshold model (3) implies breeding in an amorph for the enzyme show that “nonessential” metabolic that the flux through the metabolic β1-4-N-acetylgalactosaminyltrans- intermediates — selected GSLs with pathway can be altered by increasing the ferase (GalNAcT) that is essential for singular major synthetic and degrada- amount of residual enzyme (increase the GM2 ganglioside and globoside syn- tive pathways — can be eliminated and trickle) or by decreasing the substrate thesis. Except for male sterility and thereby decrease storage without input (drop the supply). This model late CNS storage of oligosaccharides, apparent adverse effects. Although encompasses the regional, organ, and the double homozygous mutants genetically based, Liu et al.’s approach cell levels, because of specific differential (Hexa/b–/– GalNAcT–/–) attained a near- is conceptually identical to the suc- metabolism. Also, the degree of tissue ly normal phenotype at the function- cessful dietary restriction therapies for involvement is affected by the specific al, histological, and biochemical levels. amino/organic acid disorders and to the substrate flux rates in various cellular These remarkable results offer a clas- inhibitor therapies for dyslipidemias. types. A good correlation exists between sic example of genetic epistasis, i.e., a sec- With a few notable exceptions, GSL the level of in situ residual enzymatic ondary genetic change completely storage diseases result from single activity in cell cultures, and the pheno- obscuring the genetic propensity to typic severity of LSDs (4). Simplistically, develop the primary phenotype. Sur- the less residual enzyme activity, the prisingly, the GalNAcT–/– mice lack com- more rapid the accumulation of sub- plex GSLs throughout all of develop- strate and the more severe the pheno- ment and are nearly normal. Given the type. Augmentation of the deficient apparent role of complex GSLs as mem- enzyme to levels above threshold should brane components in cellular interac- correct substrate flux, and, if reversible, tion and recognition as well as other the phenotype. The approaches of gene- major biological phenomenon (5), the based and enzyme therapies have implication that these lipids are just focused nearly exclusively on the out- decorative gives one pause. Perhaps the flow side. behavioral or biochemical tests are too The β-hexosaminidases are essential insensitive or are inappropriate to detect for degradation of the GSLs, GM2 gan- abnormalities. Nevertheless, gross dys- glioside and globoside. Mutations in the function might have been anticipated. α-chain lead to β-hexosaminidase A Such a free lunch seems doubtful. Are (α2β) deficiencies and the Tay Sachs vari- there alternative, compensatory path- ants with CNS GM2 ganglioside storage. ways? The alternative explanation that Mutations of β-chains produce deficien- mice are mice and men are men is not Figure 1 Substrate flux is determined by various input and output rates including substrate synthesis, but other factors, including alternative metabolic pathways, environmental exposures, cell type, or tissue region, etc., can significantly influence this rate. “S” indicates a steady state level of substrate that is not neces- sarily normal. A significant issue is the level of substrate that is compatible with normalcy. The rate of “S” increase determines the age of onset and progression of metabolic diseases. The Journal of Clinical Investigation | February 1999 | Volume 103 | Number 4 439 without merit, but it must be viewed in hypomorphs, i.e., affected patients with effects lead to differential phenotypes the context of the great genetic and significant residual enzyme and a late as a result of genetic epistasis or other complex GSL similarities between these (milder) phenotype. Decreasing substrate poorly defined gene–gene interactions. two species. The preservation of com- inflow might allow for less aberrant flux, Conditional expression systems allow- plex synthetic machinery for such further delaying the phenotype, and per- ing independent titration of gene apparently “non-essential” metabolites mitting longer-term functionality. Addi- expression would provide exquisite would have profound evolutionary and tion of enzyme replacement and/or gene- tools for critical analysis of gene–gene biologic implications. based therapies could provide additional interaction at an organismal level. In human GM2 gangliosidoses, stor- corrections. The latter approaches are These broader applications to a variety age is readily observed by 6 weeks of formidable challenges for CNS diseases, of pathways provide potential links gestation. Thus, postnatal therapy for because delivery of functional macro- between statistical and functional GSLs could be seriously limited by pre- molecules to the brain has proved diffi- genomics and are the fundamental existing irreversible disease. Liu et al.’s cult. Such effective therapies may provide implications of Liu et al.’s work. Hex a/b–/– GalNAcT+/– mice had signifi- hope to the families affected by substrate 1. Liu, Y., et al. 1999. A genetic model of substrate cant clinical and biochemical abnor- overload diseases. deprivation therapy for a glycosphingolipid stor- malities. This suggests the need for The basic implications and opportu- age disorder. J. Clin. Invest. 103:497–505. continuous, complete inhibition of the nities also are great. Development of a 2. Radin, N.S. 1982. Inhibitors and stimulators of glucocerebroside metabolism. Prog. Clin. Biol. Res. synthetic pathway that may not be cadre of animals with specific defects in 95:357–383. achievable by drug therapy, and com- GSL or other synthetic pathways would 3. Conzelmann, E., and Sandhoff, K. 1983. Partial plete prevention of progressive CNS dis- provide critical reagents for dissecting enzyme deficiencies: residual activities and the development of neurological disorders. Dev. Neu- ease may not be possible in postnatal and understanding metabolic patho- rosci. 6:58–71. humans. So, the postnatal approach physiology and