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Pharmacological Treatment of Monogenic Disease DJ Weatherall 265 The Pharmacogenomics Journal (2003) 3, 264–266 & 2003 Nature Publishing Group All rights reserved 1470-269X/03 $25.00 www.nature.com/tpj PERSPECTIVE or structure of the b globin chains of Pharmacological treatment adult hemoglobin. In adult life, the main hemoglobin is hemoglobin A, of monogenic disease which contains pairs of a and b chains (a2b2), while in the latter half of fetal DJ Weatherall life the main hemoglobin is hemoglo- bin F, which has pairs of a and g chains (a2g2). The switch from g to b chain Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, synthesis occurs late in pregnancy. It Oxford, UK has been known for many years that patients with serious forms of b tha- lassemia or with sickle cell anemia The Pharmacogenomics Journal (2003) 3, inherited metabolic diseases appear to who continue to produce unusually 264–266. doi:10.1038/sj.tpj.6500198 show some response to vitamins, vita- high levels of hemoglobin F, that is g min B6 for the treatment of homo- chains, after birth tend to run a milder cystinuria or thiamine for the clinical course.2,3 In the case of b Despite the rapid increase in knowl- management of maple syrup urine thalassemia, this is because the main edge of the molecular basis for mono- disease, for example. pathophysiological mechanism is glo- genic diseases over the last 10 years, These therapeutic deficiencies are bin chain imbalance with precipita- their treatment remains unsatisfac- compounded by the relative paucity tion of excess a chains that damage red tory. The latest edition of a leading of genetic diseases that can be mana- cell precursors. In sickle cell anemia, monograph on the field summarizes ged by organ transplant, and contin- on the other hand, the phenotype the position as follows: of the 570 ued difficulties and frustrations in the results from the abnormal structure conditions analysed in detail, 12% field of somatic gene therapy. Ap- of the b globin chain, which leads to showed a complete response to treat- proaches that involve selective correc- intravascular sickling and a variety of ment, 54% some partial benefit, and in tion of molecular pathology at the subsequent complications. Hemoglo- 34% there was no response at all.1 It DNA or mRNA level are promising, bin F production is valuable to b concludes that the most effective although formidable problems remain thalassemic patients because it reduces forms of management are sympto- before they can be used in the clinic, the degree of globin chain imbalance,2 matic support, substrate limitation, particularly delivery. Hence, the case and to patients with sickle cell anemia protein replacement, and a small role for exploring new pharmacological because hemoglobin F interferes with for the removal of toxic metabolites avenues seems to be stronger than the sickling process.3 via the activation of alternate path- ever. Despite a great deal of work, very ways, bone marrow transplantation, One of the more novel approaches little is known about the mechanisms and surgery. Pharmacological ap- to the pharmacological management involved in regulating the switch from proaches were only considered of of monogenic disease, not discussed g to b chain synthesis. However, many value in 10% of diseases, or less. widely in the clinical-genetics litera- years ago it was observed that patients There are, of course, good examples ture, is the attempt to reactivate recovering from bone marrow depres- of cases in which a knowledge of the genes that are utilized during fetal sion after chemotherapy for leukemia, molecular pathology of a monogenic development to replace the activity or in other states in which the bone disease has led to either definitive or of those which carry deleterious marrow was rapidly regenerating, valuable supportive approaches to mutations and which are expressed tended to produce more foetal haemo- treatment.1 They include the develop- mainly in adult life. While this globin during the period of erythroid ment of the statins or bile-binding notion has been investigated for many expansion. This led to the notion that, resins for lowering cholesterol levels in years in the abnormal hemoglobin by the perturbation of erythropoiesis patients with monogenic hypercholes- field,2,3 which encompasses the using cytotoxic agents, it might be terolemia, agents for the artificial in- most common human monogenic possible to augment the amount of hibition of the tyrosine pathway to diseases, it is only in the last few years fetal hemoglobin produced in sickle block the synthesis of toxic metabo- that some genuine progress has been cell anemia or b-thalassemia. Along lites for the management of type 1 made. the way, it was also found that babies hereditary tyrosinemia, and bipho- The two important families of in- born of diabetic mothers have higher sphonate therapy aimed at decreasing herited disorders of hemoglobin, b levels of fetal hemoglobin after birth the rate of bone turnover in patients thalassemia and sickle cell anemia, and that the agent responsible is with osteogenesis imperfecta. Several involve defects in either the synthesis probably butyrate. Could this observa- Pharmacological treatment of monogenic disease DJ Weatherall 265 tion also be utilized to augment he- summarized recently.3 In a few cases of The recent successes, albeit limited, mogobin F production after birth? b thalassemia of intermediate severity, in the management of the hemoglobin The first agent to be used to reacti- there have been spectacular increases disorders underline the importance of vate fetal hemoglobin was 5-azacyti- in hemoglobin F levels, allowing chil- determining the mechanisms for the dine, a demethylating agent.4 The dren to lead a transfusion-free life.10 remarkable phenotypic heterogeneity results were encouraging in that it Mostly, however, the responses have of monogenic diseases. In the case of produced an elevation of fetal hemo- been less spectacular, both in b thalas- the hemoglobin disorders, this has globin in a small number of patients semia and sickle cell anemia, although already led to the concept of reactiva- with sickle cell anemia, but the studies intermittent courses of arginine buty- tion of fetal hemoglobin and, in the were not pursued further because of rate have shown some promise in the future, could well lead to other ther- the potential toxicity of the agent. latter condition.11 Recently, there has apeutic approaches, the development After encouraging animal studies, hy- been a re-evaluation of the use of DNA of selective suppression of a chain droxyurea was the next drug to be demethylating agents and it has been production as a way of managing b introduced into human clinical stu- found that an analogue of 5-azacyti- thalassemia for example. The explora- dies.5 The preliminary results led to a dine, 5,aza-20-deoxycytidine (decita- tion of such experiments of nature will large-scale, multicenter trial of hydro- bine) shows promise as an inducer of be well worth pursuing in the case of xyurea for sickle cell anemia (MSH), fetal hemoglobin synthesis in patients other monogenic diseases; if the sever- which was finally closed in 1994 after with sickle cell anemia.12 Similarly, ity of their phenotypes can be reduced 13 months of observation. The results there has been a resurgence of interest by genetic or even environmental were promising; there was a reduction in the possibility of using agents that factors, it may be possible to reproduce in painful crises of about 50% and may ameliorate sickle cell anemia by these effects pharmacologically. some evidence for reduction in the their effects on the microcirculation. Although the picture is still far from frequency of other complications For example, a randomized controlled encouraging, there have been some although not, importantly, stroke.6 trial of purified poloxamer 188 has improvements in the management of This trial was followed by a number shown a significant decrease in epi- monogenic diseases over the last 20 of smaller scale studies both in adults sodes of painful crises, although the years. At the same time, we have and children, the results of which, up effects were small.13 gradually started to gain some under- to 2001, have been extensively sum- While these results are encouraging standing of their complexity and why marized.3 Very recently, the results of a there is still much to be learned about they have such varied phenotypes.15 long-term observational follow-up the application of these pharmaceuti- Such information will surely help to study of some of the original patients cal agents for the treatment of the b guide us towards more effective phar- of the MSH trial was published.7 They hemoglobinopathies. Particularly in macological approaches to their man- suggest that adults who receive hydro- the case of sickle cell anemia, it is still agement in the future. xyurea for painful sickle cell episodes not clear what levels of hemoglobin F appear to have a reduced mortality are required to produce long-term after 9 years of follow-up. Survival was control of the disease. And with our DUALITY OF INTEREST related to the level of hemoglobin F current state of knowledge, it is also None. and the frequency of vaso-occlusive not clear which patients should be events. Equally promising results have treated with hydroxyurea, or, whether Correspondence should be sent to: been obtained in a number of smaller over a very long period of administra- DJ Weatherall, Weatherall Institue of scale studies involving
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