Comment

1798 www.thelancet.com Vol 381 May 25, 2013

The number of children dying from preventable causes has fallen dramatically during the past two decades. In 2011, fewer than 7 million children younger than 5 years died from preventable causes; 20 years ago that number was 12 million.1 This progress is testament to what happens when leaders, governments, organisations, and civil society work together to save the lives of children around the world.

But we still have a long way to go. Every child lost is a tragedy for their family, their community, and their country. At a global level this loss is staggering. Every

year, pneumonia and diarrhoea alone account for the deaths of 2 million children under the age of 5 years.1 In 2011, diarrhoea caused the deaths of 700 000 children and pneumonia killed 1·3 million children.2 Most of the children who die from pneumonia and diarrhoea live in families with the lowest incomes who are under-served by health-care services and are from remote and rural areas.3

Solutions are known and cost eff ective. Yet fewer than a third of children with suspected pneumonia receive life-saving antibiotics, most high-burden

Playing our part to save children’s lives

delivery eff ectiveness, but information on effi cacy in this specifi c context is not available. Thus, the number of cells exposed to Dz13 might have been less than ideal. The liposomes used in lipid carriers are positively charged molecules that form complexes with and neutralise the negatively charged phosphate groups of the drug. This neutralisation keeps to a minimum repulsion by the negatively charged cell membrane and enables the drug to enter tumour cells. The degree of negative-charge neutralisation depends on the molar ratio between liposomes and the drug, and variation could alter the eff ectiveness of delivery. Cho and colleagues used the same amount of liposome in combination with diff erent doses of Dz13, which leads to preparations with diff erent molar ratios and might explain why outcomes with the 30 μg dose were not better than those with 10 μg. Features that could aff ect delivery need to be addressed further in eff ectiveness studies. We believe, however, that these technical points do not lessen the relevance of the study, which was designed to assess safety and tolerability.

Cho and colleagues10 show that Dz13 is a feasible and tolerated treatment for nodular basal-cell carcinoma. Although more insight into treatment effi cacy is needed, the data reported represent an important step towards bringing this DNAzyme into the clinic. Once the safety and effi cacy of Dz13 has been consolidated in further human studies, the therapeutic potential of this treatment will need to be tested in more challenging skin tumours, such as melanoma, for which eff ective treatments are not available for the advanced stages of disease in human beings.

*Gabriele Grassi, Mario GrassiDepartment of Life Sciences (GG) and Department of Industrial Engineering and Information Technology (MG), University of Trieste, Trieste 34149, Italy; and Department of Medical, Surgical and Health Sciences, University Hospital of Cattinara, Trieste, Italy (GG) ggrassi@units.it

We declare that we have no confl icts of interest.

1 Grassi M, Cavallaro G, Scirè S, et al. Current strategies to improve the effi cacy and the delivery of nucleic acid based drugs. Curr Signal Transduct Ther 2010; 5: 92–120.

2 Santoro SW, Joyce GF. A general purpose RNA-cleaving DNA enzyme. Proc Natl Acad Sci USA 1997; 94: 4262–66.

3 Achenbach JC, Chiuman W, Cruz R, Li Y. DNAzymes: from creation in vitro to application in vivo. Curr Pharm Biotechnol 2004; 5: 321–36.

4 Luo X, Cai H, Ni J, et al. c-Jun DNAzymes inhibit myocardial infl ammation, ROS generation, infarct size, and improve cardiac function after ischemia-reperfusion injury. Arterioscler Thromb Vasc Biol 2009; 29: 1836–42.

5 Zhang L, Gasper WJ, Stass SA, Ioff e OB, Davis MA, Mixson AJ. Angiogenic inhibition mediated by a DNAzyme that targets vascular endothelial growth factor receptor 2. Cancer Res 2002; 62: 5463–69.

6 Cairns MJ, Hopkins TM, Witherington C, Wang L, Sun LQ. Target site selection for an RNA-cleaving catalytic DNA. Nat Biotechnol 1999; 17: 480–86.

7 Fahmy RG, Waldman A, Zhang G, et al. Suppression of vascular permeability and infl ammation by targeting of the transcription factor c-Jun. Nat Biotechnol 2006; 24: 856–63.

8 Fahmy RG, Dass CR, Sun LQ, Chesterman CN, Khachigian LM. Transcription factor Egr-1 supports FGF-dependent angiogenesis during neovascularization and tumor growth. Nat Med 2003; 9: 1026–32.

9 Santiago FS, Lowe HC, Kavurma MM, et al. New DNA enzyme targeting Egr-1 mRNA inhibits vascular smooth muscle proliferation and regrowth after injury. Nat Med 1999; 5: 1264–69.

10 Cho E-A, Moloney FJ, Cai H, et al. Safety and tolerability of an intratumorally injected DNAzyme, Dz13, in patients with nodular basal-cell carcinoma: a phase 1 fi rst-in-human trial (DISCOVER). Lancet 2013; published online May 7. http://dx.doi.org/10.1016/S0140-6736(12)62166-7.

11 Cai H, Santiago FS, Prado-Lourenco L, et al. DNAzyme targeting c-jun suppresses skin cancer growth. Sci Transl Med 2012; 4: 139ra82.

12 Jin JY, Ke H, Hall RP, Zhang JY. c-Jun promotes whereas JunB inhibits epidermal neoplasia. J Invest Dermatol 2011; 131: 1149–58.

13 Grassi M, Grassi G, Lapasin R, Colombo I. Understanding drug release and absorption mechanisms: a physical and mathematical approach. Boca Raton, FL: CRC Press, 2006.

14 Phillips MA, Gran ML, Peppas NA. Targeted nanodelivery of drugs and diagnostics. Nano Today 2010; 5: 143–59.

Published OnlineApril 12, 2013

http://dx.doi.org/10.1016/S0140-6736(13)60719-9

See Series Lancet 2013; 381: 1415, 1417, 1487, and 1499

Comment

www.thelancet.com Vol 381 May 25, 2013 1799

countries do not have comprehensive coverage of rotavirus and pneumococcal vaccines, and about 2·5 billion people still have no access to improved sanitation facilities.4 That is why we need to recommit to tackling these causes of child mortality, comprehensively and consistently.

This Lancet Series2,5–7 renews a sense of urgency for action to make widely available and aff ordable the proven interventions that prevent and treat pneumonia and diarrhoea. If we commit to ensuring that 80% of the world’s children have access to these interventions, and if we immunise 90% of children, we will almost eliminate deaths from diarrhoea, and eliminate two thirds of all deaths from pneumonia by 2025.5 Some of the steps that need to be taken to tackle childhood pneumonia and diarrhoea are shown in the panel.

Leadership, commitment, and coordination are needed above all else. We know that more is achieved when we work together. Since 2010, when the United Nations Secretary-General launched the Every Woman Every Child initiative for women’s and children’s health, a global movement has grown of individuals, governments, and organisations that is committed to ending the preventable deaths of children. Our involvement in the UN Commission on Life-Saving Commodities for Women and Children and the UN Commission on Information and Accountability for Women’s and Children’s Health is starting to see real, tangible outcomes as a result of everyone working together.8 The international community now has fi rm recommendations about giving people access to life-saving commodities. We have common targets and approaches to accountability and transparency, improved tracking of our resources, and better measurement of results. Through the Every Woman Every Child movement we are implementing these recommendations as a global community.

The new WHO/UNICEF Integrated Global Action Plan for the Prevention and Control of Pneumonia and Diarrhoea9 will guide international eff orts to prevent children dying from these two major killers. Our eff orts will require strong national political backing, the setting of clear priorities, and long-term fi nancial investment. The results we can achieve will repay the eff ort. We will seek to draw in new partners to implement the integrated global action plan and to work with all those involved so that, within a

generation, we can celebrate a world where no child dies from the most easily preventable of diseases.

Jakaya Kikwete, *Kevin Jenkins, Jasmine Whitbread President’s Offi ce, Dar es Salaam, Tanzania (JK); World Vision International, Stockley Park, Uxbridge UB11 1FG, UK (KJ); and Save the Children International, London, UK (JW)kevin_jenkins@wvi.org

JK is the President of the United Republic of Tanzania. KJ is President and Chief Executive Offi cer of World Vision International. JW is Chief Executive Offi cer for Save the Children International. We declare that we have no confl icts of interest.

1 UNICEF, WHO, World Bank, UN. Levels and trends in child mortality: report 2012. New York: United Nations Children’s Fund, 2012.

2 Fischer Walker CL, Rudan I, Liu L, et al. Global burden of childhood pneumonia and diarrhoea. Lancet 2013; published online April 12. http://dx.doi.org/10.1016/S0140-6736(13)60222-6.

3 UNICEF. Committing to child survival: a promise renewed, progress report 2012. New York: United Nations Children’s Fund, 2012.

4 WHO, UNICEF. Countdown to 2015, building a future for women and children, the 2012 report. Geneva: World Health Organization, 2012.

5 Bhutta ZA, Das JK, Walker N, et al, for The Lancet Diarrhoea and Pneumonia Interventions Study Group. Interventions to address deaths from childhood pneumonia and diarrhoea equitably: what works and at what cost? Lancet 2013; published online April 12. http://dx.doi.org/10.1016/S0140-6736(13)60648-0.

6 Gill CJ, Young M, Schroder K, et al. Bottlenecks, barriers, and solutions: results from multicountry consultations focused on reduction of childhood pneumonia and diarrhoea deaths. Lancet 2013; published online April 12. http://dx.doi.org/10.1016/S0140-6736(13)60314-1.

7 Chopra M, Mason E, Borrazzo J, et al. Ending of preventable deaths from pneumonia and diarrhoea: an achievable goal. Lancet 2013; published online April 12. http://dx.doi.org/10.1016/S0140-6736(13)60319-0.

8 Jonathan G, Stoltenberg J. A tipping point for change: saving millions of additional lives in 2013 and beyond. Lancet 2013; 381: 350–52.

9 WHO, UNICEF. Integrated global action plan for the prevention and control of pneumonia and diarrhoea. Geneva: World Health Organization/New York: United Nations Children’s Fund, 2013.

Panel: Tackling childhood pneumonia and diarrhoea—reaching all children

• Ensure all children have access to life-saving vaccines and essential treatments such as amoxicillin for pneumonia and oral rehydration solution and zinc for diarrhoea

• Identify the poorest and hardest-to-reach communities and target them better with accessible health care

• Promote awareness and accelerate action to address the social and environmental determinants of health, for example by reducing harmful indoor air pollution produced by burning fi rewood

• Increase demand from families and communities for quality health services• Strengthen partnerships between public and private actors to encourage innovations

in, and expand the reach of, health services • Build a workforce of front-line health workers who are better trained and supported to

deliver quality services to communities, including the management of pneumonia and diarrhoea in the home and community

• Ensure that women and children know their rights to quality health care and are empowered to hold their leaders to account for any failure to deliver on their commitments

• Measure the results of tackling diarrhoea and pneumonia and compare the progress to the promises that have been made

• Continue to lobby governments and other stakeholders to ensure improved services and better health for the world’s poorest children