Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

Pharmacological treatment of monogenic disease

The Pharmacogenomics Journal volume 3, pages 264–266 (2003)Cite this article

Despite the rapid increase in knowledge of the molecular basis for monogenic diseases over the last 10 years, their treatment remains unsatisfactory. The latest edition of a leading monograph on the field summarizes the position as follows: of the 570 conditions analysed in detail, 12% showed a complete response to treatment, 54% some partial benefit, and in 34% there was no response at all.1 It concludes that the most effective forms of management are symptomatic support, substrate limitation, protein replacement, and a small role for the removal of toxic metabolites via the activation of alternate pathways, bone marrow transplantation, and surgery. Pharmacological approaches were only considered of value in 10% of diseases, or less.

There are, of course, good examples of cases in which a knowledge of the molecular pathology of a monogenic disease has led to either definitive or valuable supportive approaches to treatment.1 They include the development of the statins or bile-binding resins for lowering cholesterol levels in patients with monogenic hypercholesterolemia, agents for the artificial inhibition of the tyrosine pathway to block the synthesis of toxic metabolites for the management of type 1 hereditary tyrosinemia, and biphosphonate therapy aimed at decreasing the rate of bone turnover in patients with osteogenesis imperfecta. Several inherited metabolic diseases appear to show some response to vitamins, vitamin B6 for the treatment of homocystinuria or thiamine for the management of maple syrup urine disease, for example.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

References

  1. Treacy EP et al. Treatment of genetic disease. In: The Metabolic Basis of Inherited Disease, ed. Scriver, C.R., Beaudet, A.L., Sly, W.S., Valle, D. 8th Edn. McGraw Hill: New York 2003: 175–192.

    Google Scholar 

  2. Weatherall DJ, Clegg JB The Thalassaemia Syndromes, 4th Edn. Blackwell Scientific Publishers: Oxford 2001.

    Book  Google Scholar 

  3. Atweh GF, Schechter AN . Pharmacologic induction of fetal hemoglobin: raising the therapeutic bar in sickle cell disease. Curr Opin Hematol 2001; 8: 123–130.

    Article  CAS  Google Scholar 

  4. Ley TJ et al. 5-Azacytidine increases γ-globin synthesis and reduces the proportion of dense cells in patients with sickle cell anemia. Blood 1983; 62: 370–380.

    CAS  PubMed  Google Scholar 

  5. Platt OS et al. Hydroxyurea enhances fetal hemoglobin production in sickle cell anemia. J Clin Invest 1984; 74: 652–656.

    Article  CAS  Google Scholar 

  6. Charache S et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. N Eng J Med 1995; 332: 1317–1322.

    Article  CAS  Google Scholar 

  7. Steinberg MH et al. Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia. Risks and benefits up to 9 years of treatement. J Am Med Assoc 2003; 289: 1645–1651.

    Article  CAS  Google Scholar 

  8. Mentzer W . Bone marrow transplantation for haemoglobinopathies. Curr Opin Hematol 2000; 7: 95–100.

    Article  CAS  Google Scholar 

  9. Bradai M et al. Hydroxyurea can eliminate transfusion requirements in children with severe beta thalassemia. Blood 2003; 102: 1529–1530.

    Article  CAS  Google Scholar 

  10. Olivieri NF et al. Treatment of thalassaemia major with phenylbutyrate and hydroxyurea. Lancet 1997; 350: 491–492.

    Article  CAS  Google Scholar 

  11. Atweh GF et al. Sustained induction of fetal hemoglobin by pulse butyrate therapy in sickle cell disease. Blood 1999; 93: 1790–1797.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. DeSimone J et al. Maintenance of elevated fetal hemoglobin levels by decitabine during dose interval treatment of sickle cell anemia. Blood 2002; 99: 3905–3908.

    Article  CAS  Google Scholar 

  13. Orringer EP et al. Purified poloxamer 188 for treatment of acute vaso-occlusive crisis of sickle cell disease. A randomized controlled trial. J Am Med Assoc 2001; 286: 2099–2106.

    CAS  Google Scholar 

  14. Deconinck N et al. Expression of truncated utrophin leads to major functional improvements in dystrophin-deficient muscles of mice. Nat Med 1997; 3: 1216–1221.

    Article  CAS  Google Scholar 

  15. Weatherall DJ . Phenotype–genotype relationships in monogenic disease: lessons from the thalassaemias. Nat Rev Genet 2001; 2: 245–255.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK

    D J Weatherall

Authors
  1. D J Weatherall
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D J Weatherall.

Additional information

DUALITY OF INTEREST

None.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Weatherall, D. Pharmacological treatment of monogenic disease. Pharmacogenomics J 3, 264–266 (2003). https://doi.org/10.1038/sj.tpj.6500198

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.tpj.6500198

This article is cited by

Search

Advanced search

Quick links