- Email: [email protected]
PTC124 for cystic fibrosis – Authors' reply
Correspondence
years is indifferent. Different decisionmakers might permissibly weigh these principles differently. The complete lives system does not solve all difficult cases. No theory can do that. But it does provide a clear, systematic framework for analysing the cases and indicating what tradeoffs are being made. Gandjour grants that the rule of rescue only seems warranted if “it actually saves lives”. The rule of rescue is a means to achieving a morally important end. If another moral principle, such as youngest-first or lottery allocation, is better at saving lives, we should use that principle instead. The rule of rescue might be “inborn and intuitive.” However, having an uncritical attitude towards our intuitive impulses is a failure of the moral imagination. In addition to pity, we have many violent and unjust inborn and intuitive responses that need to be suppressed rather than indulged. Over history, public executions and displays of violence have viscerally delighted people. Accepting the inborn and intuitive might be what often allows moral injustice to go unchecked.3 We declare that we have no conflicts of interest.
Govind Persad, Alan Wertheimer, *Ezekiel J Emanuel [email protected] Department of Bioethics, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA 1
2 3
Krohmal BJ, Emanuel EJ. Access and ability to pay: the ethics of a tiered health care system. Arch Intern Med 2007; 167: 433–37. Rawls J. A theory of justice. Oxford: Oxford University Press, 1999. Glover J. Humanity: a moral history of the twentieth century. New Haven: Yale University Press, 2000.
PTC124 for cystic fibrosis
Science Photo Library
Eitan Kerem and colleagues (Aug 30, p 719)1 report encouraging results for a phase II trial of PTC124 in cystic fibrosis. Devastating diseases such as this sometimes arise when a “nonsense mutation” introduces a premature termination codon into a gene. What results is a truncated protein that can malfunction or interfere with normal 1426
proteins. PTC124 can overcome nonsense mutations without affecting normal protein synthesis.2 Premature termination codons are not always bad. They can inactivate genes in retrotransposons and endogenous retroviruses, preventing these genome “parasites” from inserting at new locations. This is fortunate since insertions can disrupt genes, alter expression, and induce rearrangements.3 LINE1 retrotransposons alone comprise 18% of our genome, and about 100 elements are capable of retrotransposition. Many other full-length copies are otherwise intact except for nonsense mutations.4 One side-effect of PTC124 might be resurrection of dormant retroelements. This possibility could be addressed preclinically using available cell culture and mouse models.5 Trials should monitor mobile element activity, and examine unexplainable health problems with a potential genetic background. Retrotransposition is derepressed in germline and embryonic cells, and consequences might appear in subsequent generations. This should be considered when following up patients. Any new treatment carries risks that can take time to assess. This was the case in 2003 when two children, although successfully treated for severe combined immunodeficiency disease by gene therapy, developed leukaemia after the retroviral vector inserted near and activated an oncogene. For PTC124, there is opportunity to monitor potential genetic risks from the beginning. We declare that we have no conflicts of interest.
*John L Goodier, Jens Mayer [email protected] Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA (JLG); and Human Genetics, Medical Faculty, University of Saar, Homburg, Germany (JM) 1
2
Kerem E, Hirawat S, Armoni S, et al. Effectiveness of PTC124 treatment of cystic fibrosis caused by nonsense mutations: a prospective phase II trial. Lancet 2008; 237: 719–27. Welch EM, Barton ER, Zhuo J, et al. PTC124 targets genetic disorders caused by nonsense mutations. Nature 2007; 447: 87–91.
3
4
5
Belancio VP, Hedges DJ, Deininger P. Mammalian non-LTR retrotransposons: for better or worse, in sickness and in health. Genome Res 2008; 18: 343–58. Brouha B, Schustak J, Badge RM, et al. Hot L1s account for the bulk of retrotransposition in the human genome. Proc Natl Acad Sci USA 2002; 100: 5280–85. Ostertag EM, DeBerardinis RJ, Goodier JL, et al. A mouse model of human L1 retrotransposition. Nat Genet 2002; 32: 655–60.
Authors’ reply PTC124 (ataluren) is a new chemical entity designed to overcome the loss of specific protein expression due to disease-causing nonsense mutations. As documented both preclinically1 and clinically (by us and others2), PTC124 acts at the level of translation, promoting the suppression of premature termination codons in mRNA without affecting normal termination codons. PTC124’s pharmacology has been extensively characterised in preclinical models,1 in healthy human volunteers,2 and, as we have shown, in patients with cystic fibrosis. Additionally, an extensive safety programme has been done. PTC124 activity and safety continues to be assessed by multiple academic investigators working in collaboration with PTC Therapeutics. A randomised study in patients with Duchenne/Becker muscular dystrophy is underway (NCT00592553) and a randomised study in patients with cystic fibrosis is expected to start shortly (NCT00803205). The development of PTC124 has been overseen by multiple health authorities, including the European Medicines Agency and the US Food and Drug Administration. These activities to assess benefit–risk notwithstanding, John Goodier and Jens Mayer raise the possibility that PTC124 could resurrect dormant retroelements that have been inactivated by nonsense mutations. Several observations indicate that the likelihood of this occurring is extremely small. First, despite the fact that aminoglycosides also promote nonsense suppression3 and many patients with cystic fibrosis receive aminoglycosides chronically by inhalation or in repeated intravenous treatments, we are www.thelancet.com Vol 373 April 25, 2009
Correspondence
EK and BK received funding support from PTC Therapeutics for this study. EMW, CT, MW, LM, and SWP are employees of PTC Therapeutics. AJ has no conflicts of interest.
*Eitan Kerem, Batsheva Kerem, Ellen M Welch, Christopher Trotta, Marla Weetall, Langdon Miller, Allan Jacobson, Stuart W Peltz [email protected] Hadassah Hebrew University Hospital, Jerusalem, Israel (EK); Department of Genetics, Life Sciences Institute, Hebrew University, Jerusalem, Israel (BK); PTC Therapeutics, South Plainfield, NJ, USA (EMW, CT, MW, LM, SWP); and Department of Molecular Genetics & Microbiology, University of Massachusetts Medical School, Worcester, MA, USA (AJ)
www.thelancet.com Vol 373 April 25, 2009
1
2
3
4
5
Welch EM, Barton ER, Zhuo J, et al. PTC124 targets genetic disorders caused by nonsense mutations. Nature 2007; 447: 87–91. Hirawat S, Welch EM, Elfring GL, et al. Safety, tolerability, and pharmacokinetics of PTC124, a non-aminoglycoside, nonsense mutation suppressor, following single- and multiple-dose administration to healthy male and female adult volunteers. J Clin Pharmacol 2007; 47: 430–14. Howard M, Frizzell RA, Bedwell DM. Aminoglycoside antibiotics restore CFTR function by overcoming premature stop mutations. Nat Med 1996; 2: 467–69. Seleme MC, Vetter MR, Cordaux R, Bastone L, Batzer MA, Kazazian HH. Extensive individual variation in L1 retrotransposition capability contributes to human genetic diversity. Proc Natl Acad Sci USA 2006; 103: 6611–16. Mendell JT, Sharifi NA, Meyers JL, Martinez-Murillo F, Dietz HC. Nonsense surveillance regulates expression of diverse classes of mammalian transcripts and mutes genomic noise. Nat Genet 2004; 36: 1073–78.
to this area, urged the Liberation Tigers of Tamil Eelam to allow civilians to leave the conflict area.5 We Sri Lankans are indeed in a crisis. In order not to make it worse, we urge the international medical community to analyse carefully the facts presented about our stricken country and help Sri Lanka to overcome this major problem. I declare that I have no conflicts of interest.
Suneth Agampodi [email protected] Department of Community Medicine, Faculty of Medicine and Allied Sciences, Rajarata University of Sri Lanka, Anuradhapura, Sri Lanka 1
Humanitarian crisis in Vanni, Sri Lanka
2
Oliver Johnson and co-authors (March 7, p 809)1 correctly point out that there is a humanitarian crisis in Sri Lanka and we are thankful to them for bringing up this important issue. However, their letter contains some inaccuracies. The UN’s announcement that cluster bombs were used on Puthukkudiyiruppu Hospital created major international concern, but the remark was later withdrawn2 and the UN resident coordinator extended an apology. Johnson and colleagues also report that humanitarian organisations have been banned by the Sri Lankan Government. The reference given for this statement actually states that “the government told all NGOs and UN to leave the area”.3 All these organisations are now based in Vavuniya, just outside the area of intense war. Not a single non-governmental organisation has actually been “banned”. Johnson and colleagues further express their concern over people entering government-held territory and being forced to remain in detention camps. However, they do not mention that terrorists are keeping civilians as hostages and have launched several attacks4 on those who try to escape from the war zones. The UN humanitarian chief, after a 3-day visit
3
4
5
Johnson O, Ratneswaren A, Beynon F. Humanitarian crisis in Vanni, Sri Lanka. Lancet 2009; 373: 809–10. Amnesty International. Update on reported use of cluster munitions in attack on hospital. http://www.amnesty.org/en/for-media/pressreleases/sri-lanka-cluster-bomb-strike-hospitaldespicable-20090204 (accessed April 6, 2009). Médecins Sans Frontières. Sri Lanka: 250,000 civilians trapped in intense fighting. http://www. msf.org.uk/civilians_trapped_in_sri_lanka_ 20090128.news (accessed March 9, 2009). UN. UN relief chief concerned over physical condition of Sri Lankans trapped by clashes. http://www.un.org/apps/news/story.asp?NewsI D=30046&Cr=sri+lanka&Cr1= (accessed March 9, 2009). UN. On visit to Sri Lanka, UN humanitarian chief stresses need to protect civilians. http://www. un.org/apps/news/story.asp?NewsID=29954&C r=sri+lanka&Cr1 (accessed March 9, 2009).
The printed journal includes an image merely for illustration PA Photos
unaware of any reports that patients treated with these drugs have become susceptible to novel suppressionmediated transpositions. Second, the frequency with which transposons are inactivated solely by a single nonsense mutation is quite low.4 PTC124 does not suppress mRNAs containing more than one premature nonsense codon.1 Third, almost all transposons harbouring a nonsense mutation have also accumulated additional mutations,4 presumably owing to a lack of selective pressure on these retroelements to maintain proteincoding potential. PTC124 does not correct protein production in transcripts containing conventional insertional, deletional, or mis-sense mutations1—ie, PTC124 is incapable of promoting the production of fulllength proteins from such elements. Finally, as Goodier and Mayer state, nonsense mutations are not always deleterious. Such mutations can mute genetic noise by promoting the degradation of nonsense-containing transcripts through the process of nonsense-mediated mRNA decay.5 Because PTC124 promotes nonsense suppression, but does not affect the nonsensemediated mRNA decay pathway,1 levels of nonsense-containing transcripts are not affected by this compound. In short, there is little scientific evidence to support the concept of retroelement activation by a drug such as PTC124.
See Editorial page 1399 See Department of Error page 1428
Assessment of childhood immunisation coverage Stephen Lim and colleagues (Dec 13, p 2031)1 recommend that, in the era of performance-based financial initiatives such as GAVI Alliance’s immunisation services support (ISS), health indicators should be monitored by independent surveys rather than administrative data-monitoring systems. However, Lim and colleagues’ estimates for immunisation coverage during the period after the onset of ISS in some low-income countries such as Cameroon are heavily weighted by pre-ISS survey data. Such estimates assume that ISS did not have an effect on the performance of immunisation programmes—an assumption that is not supported by a closer look at immunisation data from Cameroon. 1427
years is indifferent. Different decisionmakers might permissibly weigh these principles differently. The complete lives system does not solve all difficult cases. No theory can do that. But it does provide a clear, systematic framework for analysing the cases and indicating what tradeoffs are being made. Gandjour grants that the rule of rescue only seems warranted if “it actually saves lives”. The rule of rescue is a means to achieving a morally important end. If another moral principle, such as youngest-first or lottery allocation, is better at saving lives, we should use that principle instead. The rule of rescue might be “inborn and intuitive.” However, having an uncritical attitude towards our intuitive impulses is a failure of the moral imagination. In addition to pity, we have many violent and unjust inborn and intuitive responses that need to be suppressed rather than indulged. Over history, public executions and displays of violence have viscerally delighted people. Accepting the inborn and intuitive might be what often allows moral injustice to go unchecked.3 We declare that we have no conflicts of interest.
Govind Persad, Alan Wertheimer, *Ezekiel J Emanuel [email protected] Department of Bioethics, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA 1
2 3
Krohmal BJ, Emanuel EJ. Access and ability to pay: the ethics of a tiered health care system. Arch Intern Med 2007; 167: 433–37. Rawls J. A theory of justice. Oxford: Oxford University Press, 1999. Glover J. Humanity: a moral history of the twentieth century. New Haven: Yale University Press, 2000.
PTC124 for cystic fibrosis
Science Photo Library
Eitan Kerem and colleagues (Aug 30, p 719)1 report encouraging results for a phase II trial of PTC124 in cystic fibrosis. Devastating diseases such as this sometimes arise when a “nonsense mutation” introduces a premature termination codon into a gene. What results is a truncated protein that can malfunction or interfere with normal 1426
proteins. PTC124 can overcome nonsense mutations without affecting normal protein synthesis.2 Premature termination codons are not always bad. They can inactivate genes in retrotransposons and endogenous retroviruses, preventing these genome “parasites” from inserting at new locations. This is fortunate since insertions can disrupt genes, alter expression, and induce rearrangements.3 LINE1 retrotransposons alone comprise 18% of our genome, and about 100 elements are capable of retrotransposition. Many other full-length copies are otherwise intact except for nonsense mutations.4 One side-effect of PTC124 might be resurrection of dormant retroelements. This possibility could be addressed preclinically using available cell culture and mouse models.5 Trials should monitor mobile element activity, and examine unexplainable health problems with a potential genetic background. Retrotransposition is derepressed in germline and embryonic cells, and consequences might appear in subsequent generations. This should be considered when following up patients. Any new treatment carries risks that can take time to assess. This was the case in 2003 when two children, although successfully treated for severe combined immunodeficiency disease by gene therapy, developed leukaemia after the retroviral vector inserted near and activated an oncogene. For PTC124, there is opportunity to monitor potential genetic risks from the beginning. We declare that we have no conflicts of interest.
*John L Goodier, Jens Mayer [email protected] Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA (JLG); and Human Genetics, Medical Faculty, University of Saar, Homburg, Germany (JM) 1
2
Kerem E, Hirawat S, Armoni S, et al. Effectiveness of PTC124 treatment of cystic fibrosis caused by nonsense mutations: a prospective phase II trial. Lancet 2008; 237: 719–27. Welch EM, Barton ER, Zhuo J, et al. PTC124 targets genetic disorders caused by nonsense mutations. Nature 2007; 447: 87–91.
3
4
5
Belancio VP, Hedges DJ, Deininger P. Mammalian non-LTR retrotransposons: for better or worse, in sickness and in health. Genome Res 2008; 18: 343–58. Brouha B, Schustak J, Badge RM, et al. Hot L1s account for the bulk of retrotransposition in the human genome. Proc Natl Acad Sci USA 2002; 100: 5280–85. Ostertag EM, DeBerardinis RJ, Goodier JL, et al. A mouse model of human L1 retrotransposition. Nat Genet 2002; 32: 655–60.
Authors’ reply PTC124 (ataluren) is a new chemical entity designed to overcome the loss of specific protein expression due to disease-causing nonsense mutations. As documented both preclinically1 and clinically (by us and others2), PTC124 acts at the level of translation, promoting the suppression of premature termination codons in mRNA without affecting normal termination codons. PTC124’s pharmacology has been extensively characterised in preclinical models,1 in healthy human volunteers,2 and, as we have shown, in patients with cystic fibrosis. Additionally, an extensive safety programme has been done. PTC124 activity and safety continues to be assessed by multiple academic investigators working in collaboration with PTC Therapeutics. A randomised study in patients with Duchenne/Becker muscular dystrophy is underway (NCT00592553) and a randomised study in patients with cystic fibrosis is expected to start shortly (NCT00803205). The development of PTC124 has been overseen by multiple health authorities, including the European Medicines Agency and the US Food and Drug Administration. These activities to assess benefit–risk notwithstanding, John Goodier and Jens Mayer raise the possibility that PTC124 could resurrect dormant retroelements that have been inactivated by nonsense mutations. Several observations indicate that the likelihood of this occurring is extremely small. First, despite the fact that aminoglycosides also promote nonsense suppression3 and many patients with cystic fibrosis receive aminoglycosides chronically by inhalation or in repeated intravenous treatments, we are www.thelancet.com Vol 373 April 25, 2009
Correspondence
EK and BK received funding support from PTC Therapeutics for this study. EMW, CT, MW, LM, and SWP are employees of PTC Therapeutics. AJ has no conflicts of interest.
*Eitan Kerem, Batsheva Kerem, Ellen M Welch, Christopher Trotta, Marla Weetall, Langdon Miller, Allan Jacobson, Stuart W Peltz [email protected] Hadassah Hebrew University Hospital, Jerusalem, Israel (EK); Department of Genetics, Life Sciences Institute, Hebrew University, Jerusalem, Israel (BK); PTC Therapeutics, South Plainfield, NJ, USA (EMW, CT, MW, LM, SWP); and Department of Molecular Genetics & Microbiology, University of Massachusetts Medical School, Worcester, MA, USA (AJ)
www.thelancet.com Vol 373 April 25, 2009
1
2
3
4
5
Welch EM, Barton ER, Zhuo J, et al. PTC124 targets genetic disorders caused by nonsense mutations. Nature 2007; 447: 87–91. Hirawat S, Welch EM, Elfring GL, et al. Safety, tolerability, and pharmacokinetics of PTC124, a non-aminoglycoside, nonsense mutation suppressor, following single- and multiple-dose administration to healthy male and female adult volunteers. J Clin Pharmacol 2007; 47: 430–14. Howard M, Frizzell RA, Bedwell DM. Aminoglycoside antibiotics restore CFTR function by overcoming premature stop mutations. Nat Med 1996; 2: 467–69. Seleme MC, Vetter MR, Cordaux R, Bastone L, Batzer MA, Kazazian HH. Extensive individual variation in L1 retrotransposition capability contributes to human genetic diversity. Proc Natl Acad Sci USA 2006; 103: 6611–16. Mendell JT, Sharifi NA, Meyers JL, Martinez-Murillo F, Dietz HC. Nonsense surveillance regulates expression of diverse classes of mammalian transcripts and mutes genomic noise. Nat Genet 2004; 36: 1073–78.
to this area, urged the Liberation Tigers of Tamil Eelam to allow civilians to leave the conflict area.5 We Sri Lankans are indeed in a crisis. In order not to make it worse, we urge the international medical community to analyse carefully the facts presented about our stricken country and help Sri Lanka to overcome this major problem. I declare that I have no conflicts of interest.
Suneth Agampodi [email protected] Department of Community Medicine, Faculty of Medicine and Allied Sciences, Rajarata University of Sri Lanka, Anuradhapura, Sri Lanka 1
Humanitarian crisis in Vanni, Sri Lanka
2
Oliver Johnson and co-authors (March 7, p 809)1 correctly point out that there is a humanitarian crisis in Sri Lanka and we are thankful to them for bringing up this important issue. However, their letter contains some inaccuracies. The UN’s announcement that cluster bombs were used on Puthukkudiyiruppu Hospital created major international concern, but the remark was later withdrawn2 and the UN resident coordinator extended an apology. Johnson and colleagues also report that humanitarian organisations have been banned by the Sri Lankan Government. The reference given for this statement actually states that “the government told all NGOs and UN to leave the area”.3 All these organisations are now based in Vavuniya, just outside the area of intense war. Not a single non-governmental organisation has actually been “banned”. Johnson and colleagues further express their concern over people entering government-held territory and being forced to remain in detention camps. However, they do not mention that terrorists are keeping civilians as hostages and have launched several attacks4 on those who try to escape from the war zones. The UN humanitarian chief, after a 3-day visit
3
4
5
Johnson O, Ratneswaren A, Beynon F. Humanitarian crisis in Vanni, Sri Lanka. Lancet 2009; 373: 809–10. Amnesty International. Update on reported use of cluster munitions in attack on hospital. http://www.amnesty.org/en/for-media/pressreleases/sri-lanka-cluster-bomb-strike-hospitaldespicable-20090204 (accessed April 6, 2009). Médecins Sans Frontières. Sri Lanka: 250,000 civilians trapped in intense fighting. http://www. msf.org.uk/civilians_trapped_in_sri_lanka_ 20090128.news (accessed March 9, 2009). UN. UN relief chief concerned over physical condition of Sri Lankans trapped by clashes. http://www.un.org/apps/news/story.asp?NewsI D=30046&Cr=sri+lanka&Cr1= (accessed March 9, 2009). UN. On visit to Sri Lanka, UN humanitarian chief stresses need to protect civilians. http://www. un.org/apps/news/story.asp?NewsID=29954&C r=sri+lanka&Cr1 (accessed March 9, 2009).
The printed journal includes an image merely for illustration PA Photos
unaware of any reports that patients treated with these drugs have become susceptible to novel suppressionmediated transpositions. Second, the frequency with which transposons are inactivated solely by a single nonsense mutation is quite low.4 PTC124 does not suppress mRNAs containing more than one premature nonsense codon.1 Third, almost all transposons harbouring a nonsense mutation have also accumulated additional mutations,4 presumably owing to a lack of selective pressure on these retroelements to maintain proteincoding potential. PTC124 does not correct protein production in transcripts containing conventional insertional, deletional, or mis-sense mutations1—ie, PTC124 is incapable of promoting the production of fulllength proteins from such elements. Finally, as Goodier and Mayer state, nonsense mutations are not always deleterious. Such mutations can mute genetic noise by promoting the degradation of nonsense-containing transcripts through the process of nonsense-mediated mRNA decay.5 Because PTC124 promotes nonsense suppression, but does not affect the nonsensemediated mRNA decay pathway,1 levels of nonsense-containing transcripts are not affected by this compound. In short, there is little scientific evidence to support the concept of retroelement activation by a drug such as PTC124.
See Editorial page 1399 See Department of Error page 1428
Assessment of childhood immunisation coverage Stephen Lim and colleagues (Dec 13, p 2031)1 recommend that, in the era of performance-based financial initiatives such as GAVI Alliance’s immunisation services support (ISS), health indicators should be monitored by independent surveys rather than administrative data-monitoring systems. However, Lim and colleagues’ estimates for immunisation coverage during the period after the onset of ISS in some low-income countries such as Cameroon are heavily weighted by pre-ISS survey data. Such estimates assume that ISS did not have an effect on the performance of immunisation programmes—an assumption that is not supported by a closer look at immunisation data from Cameroon. 1427