A novel treatment of cystic fibrosis acting on-target: cysteamine plus epigallocatechin gallate for the autophagy-dependent rescue of class II-mutated CFTR.

This corrects the article DOI: 10.1038/cdd.2016.22.

A novel treatment of cystic fibrosis acting on-target: cysteamine plus epigallocatechin gallate for the autophagy-dependent rescue of class II-mutated CFTR.

We previously reported that the combination of two safe proteostasis regulators, cysteamine and epigallocatechin gallate (EGCG), can be used to improve deficient expression of the cystic fibrosis transmembrane conductance regulator (CFTR) in patients homozygous for the CFTR Phe508del mutation. Here we provide the proof-of-concept that this combination treatment restored CFTR function and reduced lung inflammation (P<0.001) in Phe508del/Phe508del or Phe508del/null-Cftr (but not in Cftr-null mice), provided that such mice were autophagy-competent. Primary nasal cells from patients bearing different class II CFTR mutations, either in homozygous or compound heterozygous form, responded to the treatment in vitro. We assessed individual responses to cysteamine plus EGCG in a single-centre, open-label phase-2 trial. The combination treatment decreased sweat chloride from baseline, increased both CFTR protein and function in nasal cells, restored autophagy in such cells, decreased CXCL8 and TNF-α in the sputum, and tended to improve respiratory function. These positive effects were particularly strong in patients carrying Phe508del CFTR mutations in homozygosity or heterozygosity. However, a fraction of patients bearing other CFTR mutations failed to respond to therapy. Importantly, the same patients whose primary nasal brushed cells did not respond to cysteamine plus EGCG in vitro also exhibited deficient therapeutic responses in vivo. Altogether, these results suggest that the combination treatment of cysteamine plus EGCG acts 'on-target' because it can only rescue CFTR function when autophagy is functional (in mice) and improves CFTR function when a rescuable protein is expressed (in mice and men). These results should spur the further clinical development of the combination treatment.

A new European perspective of influenza pandemic planning with a particular focus on the role of mammalian cell culture vaccines.

Sixteen EU scientists and doctors were interviewed about pandemic planning using psychometric methods applied to a scientific problem for the first time. Criticism was aimed at countries which have no plan whatsoever, the majority of nations. Many such countries have not invested in scientific infrastructure and public health. Amongst the 15 or so published pandemic plans a lack of detail was identified. Of particular need was investment into avian virus vaccine stocks (H1-15), prepared licenses of vaccine and pre purchase and agreed distribution, investment into stocks of antivirals, antibiotics and masks. Most but not all members of the group predicted a global outbreak within 5 years, most probably starting in SE Asia. However it was recognised that a pandemic could start anywhere in the world which had juxtaposition of young people, chickens, ducks and pigs. Mammalian cell culture production using wild type virus with the production factory at category III levels of security was exemplified. Antivirals would be essential to ameliorate the first wave of infection although significant quantities of cell grown vaccine could be produced if, as in 1918, 1957 and 1968 there is a long period between the first virus isolation and person to person spread. The wider scientific community is more energised than previously for very serious preparations to be in place way before the outbreak begins as this is a major public health problem, completely dwarfing concerns about bioterrorism.

Environmental surveillance of poliovirus in Italy: pilot study.

A pilot study on environmental surveillance of poliovirus included one hundred ninety-six samples (drinking water, surface water, seawater and sewage), collected between 1996 and 1998 in different regions of Italy. Samples were screened for the presence of poliovirus and other enteric viruses. Twelve polioviruses, 35 non polio enteroviruses (NPE) and 51 enteric non entero (NE) viruses were isolated. All poliovirus isolates, namely four type 1, four type 2 and four type 3, were characterised as Sabin-like strains. Thirty-one Coxsackie B and 4 Echo viruses were also detected. The presence of Sabin-like polioviruses in the environment is not unexpected since immunization with only oral poliovirus vaccine was performed in Italy until May 1999, when a sequential schedule consisting of two doses of inactivated polio vaccine (IPV) and two of oral polio vaccine (OPV) was adopted; in July 2002 a schedule consisting of four doses of IPV was adopted. Although this is only a pilot study and the number of samples analysed is limited, so far data from this study so far supports once again evidence of lack of circulating wild poliovirus and is in line with results from AFP surveillance in Italy and stool survey on healthy children.

Risk management of HBsAg or anti-HCV positive healthcare workers in hospital.

Recommendations are made for controlling the transmission of the hepatitis B and hepatitis C viruses from healthcare workers to patients. These recommendations were based both on the literature and on experts' opinions, obtained during a Consensus Conference. The quality of the published information and of the experts' opinions was classified into 6 levels, based on the source of the information. The recommendations can be summarised as follows: all healthcare workers must undergo hepatitis B virus vaccination and adopt the standard measures for infection control in hospitals; healthcare workers who directly perform invasive procedures must undergo serological testing and the evaluation of markers of viral infection. Those found to be positive for: 1) HBsAg and HBeAg, 2) HBsAg and hepatitis B virus DNA, or 3) anti-hepatitis C virus and hepatitis C virus RNA must abstain from directly performing invasive procedures; no other limitations in their activities are necessary. Infected healthcare workers are urged to inform their patients of their infectious status, although this is left to the discretion of the healthcare worker; whose privacy is guaranteed by law. If exposure to hepatitis B virus occurs, the healthcare worker must undergo prophylaxis with specific immunoglobulins, in addition to vaccination.

Enterovirus surveillance of Italian healthy children.

Surveillance of acute flaccid paralysis (AFP) is the golden strategy recommended by the WHO to verify the condition of polio eradication in a country. Because of the difficulty to detect all of the expected AFP cases and to reach the target incidence of 1/100,000 requested by WHO, the surveillance of enteroviruses in the population has been adopted by several countries as an important additional method to verify the absence of wild-poliovirus circulation. To complete the results of AFP surveillance set up in Italy in 1996, we have conducted a wild poliovirus surveillance by examining stool samples from 1551 healthy children aged less than 5 years, collected during the period January 1997 to January 1998. The children were from three cities (Parma, Rome and Bari) located in northern, central and southern Italy. Thirty-nine polioviruses, 72 non-polio enteroviruses and 50 enteric, nonentero (NE), viruses were isolated from stool specimens. Polioviruses identified were nine type 1, seven type 2 and twenty-three type 3. Characterization of isolates by both antigenic and molecular methods showed that all polioviruses were of vaccine origin. As expected, most polioviruses, especially types 2 and 3, presented retromutations known to be associated with loss of the Sabin attenuated phenotype. The results of this study support the data obtained from the active AFP surveillance conducted in Italy in the same period--on the absence of paralytic disease due to wild poliovirus--and altogether demonstrate the effectiveness of the vaccination program.

Surveillance of acute flaccid paralysis in Italy: 1996-1997. AFP Study Group. Acute flaccid paralysis.

The last case of poliomyelitis due to transmission of indigenous wild poliovirus occurred in Italy in 1982. To achieve the certification of the eradication of poliomyelitis in Italy, an active surveillance of acute flaccid paralysis (AFP) in the population aged less than 15 years was set up following the World Health Organization (WHO) guidelines. The survey started in 1996 with a pilot study involving 4 out of 21 regions, and was gradually extended to a national level in 1997. The two-year survey identified five patients with diagnosis of vaccine associated paralytic poliomyelitis (VAPP). Polioviruses type 2 and 3 Sabin-like were isolated and characterized in three of them. In the remaining two cases, samples were collected late after the onset of symptoms, and poliovirus could not be isolated. No wild polioviruses were detected during the survey. The rate of non-polio AFP found in Italy in 1997 was 0.61 cases per 100,000, which is lower than the level of 1.0 case per 100,000 considered as acceptable by the WHO. This was mainly due to the delay in organizing the hospital network and starting the active search of AFP cases in the largest and most densely populated regions. Therefore, the overall rate of AFP found in Italy underestimates the global effectiveness of the program, which however will be better evaluated in the next few years. This study is the first systematic attempt to determine the rate of AFP in Italy.