Safe drugs to fight mutant protein overload and alpha-1-antitrypsin deficiency

Abstract

Drug enhanced autophagy to fight mutant protein overloadJournal of HepatologyVol. 54Issue 5PreviewCOMMENTARY ON: An autophagy-enhancing drug promotes degradation of mutant alpha1-antitrypsin Z and reduces hepatic fibrosis. Hidvegi T, Ewing M, Hale P, Dippold C, Beckett C, Kemp C, Maurice N, Mukherjee A, Goldbach C, Watkins S, Michalopoulos G, Perlmutter DH. Science 2010;329(5988):229–32. Abstract reprinted with permission from the AAAS. Full-Text PDF Open Access We read with interest the commentary, “Drug enhanced autophagy to fight mutant protein overload”, by Mehrpour and Codogno [[1]Mehrpour M. Codogno P. Drug enhanced autophagy to fight mutant protein overload.J Hepatol. 2011; 54: 1066-1068Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar]. The authors discuss recent experimental findings by Hidvegi et al., in a in vitro and in an animal model of alpha-1-antitrypsin (AT) deficiency, which raise the interesting possibility that the iminostilbene derivative carbamazepine (CBZ) could be used to treat this severe liver disease in humans [1Mehrpour M. Codogno P. Drug enhanced autophagy to fight mutant protein overload.J Hepatol. 2011; 54: 1066-1068Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar, 2Hidvegi T. Ewing M. Hale P. Dippold C. Beckett C. Kemp C. et al.An autophagy-enhancing drug promotes degradation of mutant alpha1-antitrypsin Z and reduces hepatic fibrosis.Science. 2010; 329: 229-232Crossref PubMed Scopus (466) Google Scholar]. The authors correctly conclude that these findings have provided the rationale for studies on CBZ in patients with AT deficiency [[1]Mehrpour M. Codogno P. Drug enhanced autophagy to fight mutant protein overload.J Hepatol. 2011; 54: 1066-1068Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar]. However, in our opinion, they overlooked that at least one crucial, open question remains to be clarified, before application of these findings in clinical practice. This concerns the fact that in the preclinical mouse model of AT deficiency, used for evaluating the CBZ effects, the results have been obtained with doses of the drug significantly higher than the doses used in humans (200 mg/kg/day vs. 10–20 mg/kg/day), lower doses of CBZ have not been effective, and in the study, the plasma levels of CBZ have not been evaluated [1Mehrpour M. Codogno P. Drug enhanced autophagy to fight mutant protein overload.J Hepatol. 2011; 54: 1066-1068Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar, 2Hidvegi T. Ewing M. Hale P. Dippold C. Beckett C. Kemp C. et al.An autophagy-enhancing drug promotes degradation of mutant alpha1-antitrypsin Z and reduces hepatic fibrosis.Science. 2010; 329: 229-232Crossref PubMed Scopus (466) Google Scholar]. However, it is worth noting that as stated by Hidvegi et al. in the discussion section of their paper [[2]Hidvegi T. Ewing M. Hale P. Dippold C. Beckett C. Kemp C. et al.An autophagy-enhancing drug promotes degradation of mutant alpha1-antitrypsin Z and reduces hepatic fibrosis.Science. 2010; 329: 229-232Crossref PubMed Scopus (466) Google Scholar], “Effective doses of drugs can be 10- to 20-fold higher in mice because of the higher ratio of surface area to weight when compared to humans”, and that the findings from preclinical and clinical studies exemplified in Table 1 fit this statement.Table 1Oral doses and plasma therapeutic levels of carbamazepine in preclinical and clinical studies.KA, kainic acid-induced; M ± S.D., mean ± standard deviation; MES, maximal electroshock seizure; M ± S.E., mean ± standard error. Open table in a new tab CBZ is a safe drug with a wide clinical spectrum of action which ranges from epileptic seizures to cerebellar tremors and myotonia [3Cereghino J.J. Brock J.T. Van Meter JC Penry J.K. Smith L.D. White B.G. Carbamazepine for epilepsy. A controlled prospective evaluation.Neurology. 1974; 24: 401-410Crossref PubMed Google Scholar, 4Sechi G.P. Zuddas M. Piredda M. Agnetti V. Sau G. Piras M.L. et al.Treatment of cerebellar tremors with carbamazepine: a controlled trial with long-term follow-up.Neurology. 1989; 39: 1113-1115Crossref PubMed Google Scholar, 5Sechi G.P. Traccis S. Durelli L. Monaco F. Mutani R. Carbamazepine versus diphenylhydantoin in the treatment of myotonia.Eur Neurol. 1983; 22: 113-118Crossref PubMed Scopus (35) Google Scholar], with well-known plasma therapeutic levels in each of these pathologies [3Cereghino J.J. Brock J.T. Van Meter JC Penry J.K. Smith L.D. White B.G. Carbamazepine for epilepsy. A controlled prospective evaluation.Neurology. 1974; 24: 401-410Crossref PubMed Google Scholar, 4Sechi G.P. Zuddas M. Piredda M. Agnetti V. Sau G. Piras M.L. et al.Treatment of cerebellar tremors with carbamazepine: a controlled trial with long-term follow-up.Neurology. 1989; 39: 1113-1115Crossref PubMed Google Scholar, 5Sechi G.P. Traccis S. Durelli L. Monaco F. Mutani R. Carbamazepine versus diphenylhydantoin in the treatment of myotonia.Eur Neurol. 1983; 22: 113-118Crossref PubMed Scopus (35) Google Scholar]. In particular, an analysis of the relationship between CBZ doses per body weight, necessary for clinical effects and CBZ plasma levels, indicates that in humans severe neurological and cardiovascular effects are usually seen at CBZ daily doses higher than 20 mg/kg, and at plasma CBZ levels greater than 12 μg/ml [6Holmes G.L. Carbamazepine. Adverse effects.in: Levy R.H. Mattson R.H. Meldrum B.S. Perucca E. Antiepileptic drugs. 5th ed. Lippincott Williams and Wilkins, Philadelphia2002: 285-297Google Scholar, 7Tibbals J. Acute toxic reaction to carbamazepine: clinical effects and serum concentrations.J Pediatr. 1992; 121: 295-299Abstract Full Text PDF PubMed Scopus (46) Google Scholar].Oral doses and plasma therapeutic levels of CBZ in preclinical and clinical studies are shown in Table 1. In preclinical studies, oral doses of CBZ seem poor predictive of plasma concentrations of the drug, likely due to the very different bioavailability of oral CBZ preparations used in the different studies. Thus, in preclinical studies, the determination of plasma CBZ concentrations seems particularly advisable. In clinical studies, instead, some relationship between oral doses of CBZ and therapeutic plasma levels seems evident.At present, the determination of plasma CBZ levels is a routinary and rather easy task both in clinical and experimental settings [3Cereghino J.J. Brock J.T. Van Meter JC Penry J.K. Smith L.D. White B.G. Carbamazepine for epilepsy. A controlled prospective evaluation.Neurology. 1974; 24: 401-410Crossref PubMed Google Scholar, 4Sechi G.P. Zuddas M. Piredda M. Agnetti V. Sau G. Piras M.L. et al.Treatment of cerebellar tremors with carbamazepine: a controlled trial with long-term follow-up.Neurology. 1989; 39: 1113-1115Crossref PubMed Google Scholar, 5Sechi G.P. Traccis S. Durelli L. Monaco F. Mutani R. Carbamazepine versus diphenylhydantoin in the treatment of myotonia.Eur Neurol. 1983; 22: 113-118Crossref PubMed Scopus (35) Google Scholar], and further studies on the therapeutic plasma levels of CBZ in preclinical animal models of AT deficiency could help to improve the quality of clinical trials aimed at assessing the efficacy of CBZ in patients with liver disease as a result of AT deficiency.Moreover, another relevant question the authors discussed in the commentary is that the findings by Hidvegi et al. also provide a proof of principle for therapeutic use of other safe autophagy enhancer drugs, potentially useful to fight protein overload in different genetic diseases [[1]Mehrpour M. Codogno P. Drug enhanced autophagy to fight mutant protein overload.J Hepatol. 2011; 54: 1066-1068Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar]. Interestingly, the β-lactam antibiotic ceftriaxone, commonly used for decades in patients with moderate to severe exacerbations of chronic obstructive pulmonary disease related to AT deficiency [[8]Hunter M.H. King D.E. COPD: management of acute exacerbations and chronic stable disease.Am Fam Physician. 2001; 64: 603-613PubMed Google Scholar], was recently shown to also be able to eliminate the toxic effects of misfolded glial fibrillary acidic protein (GFAP) in a cellular model of Alexander disease, a rare, usually fatal neurodegenerative disorder, by decreasing GFAP intracytoplasmic aggregates, through complex biochemical mechanisms involving GFAP promoter down-regulation and enhancement of autophagy [9Bachetti T. Di Zanni E. Balbi P. Bocca P. Prigione I. Deiana G.A. et al.In vitro treatments with ceftriaxone promote elimination of mutant glial fibrillary acidic protein and transcription down-regulation.Exp Cell Res. 2010; 316: 2152-2165Crossref PubMed Scopus (32) Google Scholar, 10Sechi G.P. Matta M. Deiana G.A. Balbi P. Bachetti T. Di Zanni E. et al.Ceftriaxone has a therapeutic role in Alexander disease.Prog Neuropsychopharmacol Biol Psychiatry. 2010; 34: 416-417Crossref PubMed Scopus (13) Google Scholar]. The question is now whether ceftriaxone will also be useful in treating other diseases caused by intracellular accumulation and aggregation of misfolded proteins such as AT deficiency.Conflict of interestThe author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. We read with interest the commentary, “Drug enhanced autophagy to fight mutant protein overload”, by Mehrpour and Codogno [[1]Mehrpour M. Codogno P. Drug enhanced autophagy to fight mutant protein overload.J Hepatol. 2011; 54: 1066-1068Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar]. The authors discuss recent experimental findings by Hidvegi et al., in a in vitro and in an animal model of alpha-1-antitrypsin (AT) deficiency, which raise the interesting possibility that the iminostilbene derivative carbamazepine (CBZ) could be used to treat this severe liver disease in humans [1Mehrpour M. Codogno P. Drug enhanced autophagy to fight mutant protein overload.J Hepatol. 2011; 54: 1066-1068Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar, 2Hidvegi T. Ewing M. Hale P. Dippold C. Beckett C. Kemp C. et al.An autophagy-enhancing drug promotes degradation of mutant alpha1-antitrypsin Z and reduces hepatic fibrosis.Science. 2010; 329: 229-232Crossref PubMed Scopus (466) Google Scholar]. The authors correctly conclude that these findings have provided the rationale for studies on CBZ in patients with AT deficiency [[1]Mehrpour M. Codogno P. Drug enhanced autophagy to fight mutant protein overload.J Hepatol. 2011; 54: 1066-1068Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar]. However, in our opinion, they overlooked that at least one crucial, open question remains to be clarified, before application of these findings in clinical practice. This concerns the fact that in the preclinical mouse model of AT deficiency, used for evaluating the CBZ effects, the results have been obtained with doses of the drug significantly higher than the doses used in humans (200 mg/kg/day vs. 10–20 mg/kg/day), lower doses of CBZ have not been effective, and in the study, the plasma levels of CBZ have not been evaluated [1Mehrpour M. Codogno P. Drug enhanced autophagy to fight mutant protein overload.J Hepatol. 2011; 54: 1066-1068Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar, 2Hidvegi T. Ewing M. Hale P. Dippold C. Beckett C. Kemp C. et al.An autophagy-enhancing drug promotes degradation of mutant alpha1-antitrypsin Z and reduces hepatic fibrosis.Science. 2010; 329: 229-232Crossref PubMed Scopus (466) Google Scholar]. However, it is worth noting that as stated by Hidvegi et al. in the discussion section of their paper [[2]Hidvegi T. Ewing M. Hale P. Dippold C. Beckett C. Kemp C. et al.An autophagy-enhancing drug promotes degradation of mutant alpha1-antitrypsin Z and reduces hepatic fibrosis.Science. 2010; 329: 229-232Crossref PubMed Scopus (466) Google Scholar], “Effective doses of drugs can be 10- to 20-fold higher in mice because of the higher ratio of surface area to weight when compared to humans”, and that the findings from preclinical and clinical studies exemplified in Table 1 fit this statement. KA, kainic acid-induced; M ± S.D., mean ± standard deviation; MES, maximal electroshock seizure; M ± S.E., mean ± standard error. CBZ is a safe drug with a wide clinical spectrum of action which ranges from epileptic seizures to cerebellar tremors and myotonia [3Cereghino J.J. Brock J.T. Van Meter JC Penry J.K. Smith L.D. White B.G. Carbamazepine for epilepsy. A controlled prospective evaluation.Neurology. 1974; 24: 401-410Crossref PubMed Google Scholar, 4Sechi G.P. Zuddas M. Piredda M. Agnetti V. Sau G. Piras M.L. et al.Treatment of cerebellar tremors with carbamazepine: a controlled trial with long-term follow-up.Neurology. 1989; 39: 1113-1115Crossref PubMed Google Scholar, 5Sechi G.P. Traccis S. Durelli L. Monaco F. Mutani R. Carbamazepine versus diphenylhydantoin in the treatment of myotonia.Eur Neurol. 1983; 22: 113-118Crossref PubMed Scopus (35) Google Scholar], with well-known plasma therapeutic levels in each of these pathologies [3Cereghino J.J. Brock J.T. Van Meter JC Penry J.K. Smith L.D. White B.G. Carbamazepine for epilepsy. A controlled prospective evaluation.Neurology. 1974; 24: 401-410Crossref PubMed Google Scholar, 4Sechi G.P. Zuddas M. Piredda M. Agnetti V. Sau G. Piras M.L. et al.Treatment of cerebellar tremors with carbamazepine: a controlled trial with long-term follow-up.Neurology. 1989; 39: 1113-1115Crossref PubMed Google Scholar, 5Sechi G.P. Traccis S. Durelli L. Monaco F. Mutani R. Carbamazepine versus diphenylhydantoin in the treatment of myotonia.Eur Neurol. 1983; 22: 113-118Crossref PubMed Scopus (35) Google Scholar]. In particular, an analysis of the relationship between CBZ doses per body weight, necessary for clinical effects and CBZ plasma levels, indicates that in humans severe neurological and cardiovascular effects are usually seen at CBZ daily doses higher than 20 mg/kg, and at plasma CBZ levels greater than 12 μg/ml [6Holmes G.L. Carbamazepine. Adverse effects.in: Levy R.H. Mattson R.H. Meldrum B.S. Perucca E. Antiepileptic drugs. 5th ed. Lippincott Williams and Wilkins, Philadelphia2002: 285-297Google Scholar, 7Tibbals J. Acute toxic reaction to carbamazepine: clinical effects and serum concentrations.J Pediatr. 1992; 121: 295-299Abstract Full Text PDF PubMed Scopus (46) Google Scholar]. Oral doses and plasma therapeutic levels of CBZ in preclinical and clinical studies are shown in Table 1. In preclinical studies, oral doses of CBZ seem poor predictive of plasma concentrations of the drug, likely due to the very different bioavailability of oral CBZ preparations used in the different studies. Thus, in preclinical studies, the determination of plasma CBZ concentrations seems particularly advisable. In clinical studies, instead, some relationship between oral doses of CBZ and therapeutic plasma levels seems evident. At present, the determination of plasma CBZ levels is a routinary and rather easy task both in clinical and experimental settings [3Cereghino J.J. Brock J.T. Van Meter JC Penry J.K. Smith L.D. White B.G. Carbamazepine for epilepsy. A controlled prospective evaluation.Neurology. 1974; 24: 401-410Crossref PubMed Google Scholar, 4Sechi G.P. Zuddas M. Piredda M. Agnetti V. Sau G. Piras M.L. et al.Treatment of cerebellar tremors with carbamazepine: a controlled trial with long-term follow-up.Neurology. 1989; 39: 1113-1115Crossref PubMed Google Scholar, 5Sechi G.P. Traccis S. Durelli L. Monaco F. Mutani R. Carbamazepine versus diphenylhydantoin in the treatment of myotonia.Eur Neurol. 1983; 22: 113-118Crossref PubMed Scopus (35) Google Scholar], and further studies on the therapeutic plasma levels of CBZ in preclinical animal models of AT deficiency could help to improve the quality of clinical trials aimed at assessing the efficacy of CBZ in patients with liver disease as a result of AT deficiency. Moreover, another relevant question the authors discussed in the commentary is that the findings by Hidvegi et al. also provide a proof of principle for therapeutic use of other safe autophagy enhancer drugs, potentially useful to fight protein overload in different genetic diseases [[1]Mehrpour M. Codogno P. Drug enhanced autophagy to fight mutant protein overload.J Hepatol. 2011; 54: 1066-1068Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar]. Interestingly, the β-lactam antibiotic ceftriaxone, commonly used for decades in patients with moderate to severe exacerbations of chronic obstructive pulmonary disease related to AT deficiency [[8]Hunter M.H. King D.E. COPD: management of acute exacerbations and chronic stable disease.Am Fam Physician. 2001; 64: 603-613PubMed Google Scholar], was recently shown to also be able to eliminate the toxic effects of misfolded glial fibrillary acidic protein (GFAP) in a cellular model of Alexander disease, a rare, usually fatal neurodegenerative disorder, by decreasing GFAP intracytoplasmic aggregates, through complex biochemical mechanisms involving GFAP promoter down-regulation and enhancement of autophagy [9Bachetti T. Di Zanni E. Balbi P. Bocca P. Prigione I. Deiana G.A. et al.In vitro treatments with ceftriaxone promote elimination of mutant glial fibrillary acidic protein and transcription down-regulation.Exp Cell Res. 2010; 316: 2152-2165Crossref PubMed Scopus (32) Google Scholar, 10Sechi G.P. Matta M. Deiana G.A. Balbi P. Bachetti T. Di Zanni E. et al.Ceftriaxone has a therapeutic role in Alexander disease.Prog Neuropsychopharmacol Biol Psychiatry. 2010; 34: 416-417Crossref PubMed Scopus (13) Google Scholar]. The question is now whether ceftriaxone will also be useful in treating other diseases caused by intracellular accumulation and aggregation of misfolded proteins such as AT deficiency. Conflict of interestThe author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.