Deybach, J.C. (Jean-Charles)
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- EXPLORE: A prospective, multinational natural history study of patients with acute hepatic porphyria with recurrent attacks(Elsevier, 2020) Bonkovsky, H.L. (Herbert L.); Badminton, M. (Michael); Ko, J. (John); Ventura, P. (Paolo); Ivanova, A. (Aneta); Penz, C. (Craig); Alegre, F. (Félix); Deybach, J.C. (Jean-Charles); Liu, S. (Shanbing); Langendonk, J.G. (Janneke G.); Anderson, K.E. (Karl E.); Montgomery-Bissell, D. (D.); Andersen, J. (Janice); Lin, T. (Tim); Rees, D.C. (David C.); Querbes, W. (William); Chan, A. (Amy); Phillips, J.D. (John D.); Aarsand, A.K. (Aasne K.); Bruha, R. (Radan); Parker, C. (Charles); Naik, H. (Hetanshi); Desnick, R.J. (Robert J.); Stölzel, U. (Ulrich); Simon, A. (Amy); Minder, E. (Elisabeth); Gouya, L. (Laurent); Talbi, N. (Neila); Cappellini, M.D. (Maria Domenica); Stein, P.E. (Penelope E.); Sardh, E. (Eliane); Sandberg, S. (Sverre); Windyga, J. (Jerzy); Balwani, M. (Manisha); Harper, P. (Pauline); Kauppinen, R. (Raili)BACKGROUND AND AIMS: Acute hepatic porphyria comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long-term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients. APPROACH AND RESULTS: EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months before the study, patients reported a median (range) of 6 (0-52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a health care facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic δ-aminolevulinic acid synthase 1 messenger ribonucleic acid levels, δ-aminolevulinic acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased health care utilization. CONCLUSIONS: Patients experienced attacks often requiring treatment in a health care facility and/or with hemin, as well as chronic symptoms that adversely influenced day-to-day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies. (Hepatology 2020;71:1546-1558).
- Current and innovative emerging therapies for porphyrias with hepatic involvement(2019) Deybach, J.C. (Jean-Charles); Anderson, K.E. (Karl E.); Avila, M.A. (Matías Antonio); Fontanellas-Romá, A. (Antonio)Porphyrias are rare inherited disorders caused by specific enzyme dysfunctions in the haem synthesis pathway, which result in abnormal accumulation of specific pathway intermediates. The symptoms depend upon the chemical characteristics of these substances. Porphyrins are photoreactive and cause photocutaneous lesions on sunlight-exposed areas, whereas accumulation of porphyrin precursors is related to acute neurovisceral attacks. Current therapies are suboptimal and mostly address symptoms rather than underlying disease mechanisms. Advances in the understanding of the molecular bases and pathogenesis of porphyrias have paved the way for the development of new therapeutic strategies. In this Clinical Trial Watch we summarise the basic principles of these emerging approaches and what is currently known about their application to porphyrias of hepatic origin or with hepatic involvement.
- Exploring current and emerging therapies for porphyrias(John Wiley & Sons, 2024) Deybach, J.C. (Jean-Charles); Anderson, K.E. (Karl E.); Avila, M.A. (Matías Antonio); Córdoba, K.M. (Karol M.); Urigo, F. (Francesco); Enriquez-de-Salamanca, R. (Rafael); Fontanellas-Romá, A. (Antonio); Jericó-Asenjo, D. (Daniel)Porphyrias are rare, mostly inherited disorders resulting from altered activity of specific enzymes in the haem synthesis pathway that lead to accumulation of pathway intermediates. Photocutaneous symptoms occur when excess amounts of photoreactive porphyrins circulate in the blood to the skin, whereas increases in potentially neurotoxic porphyrin precursors are associated with neurovisceral symptoms. Current therapies are suboptimal and their mechanisms are not well established. As described here, emerging therapies address underlying disease mechanisms by introducing a gene, RNA or other specific molecule with the potential to cure or slow progression of the disease. Recent progress in nanotechnology and nanoscience, particularly regarding particle design and formulation, is expanding disease targets. More secure and efficient drug delivery systems have extended our toolbox for transferring specific molecules, especially into hepatocytes, and led to proof-of-concept studies in animal models. Repurposing existing drugs as molecular chaperones or haem synthesis inhibitors is also promising. This review summarizes key examples of these emerging therapeutic approaches and their application for hepatic and erythropoietic porphyrias.