Emerging Disease-Modifying Therapies in Neurodegeneration With Brain Iron Accumulation (NBIA) Disorders

Vassilena Iankova, Ivan Karin, Thomas Klopstock, Susanne A Schneider, Vassilena Iankova, Ivan Karin, Thomas Klopstock, Susanne A Schneider

Abstract

Neurodegeneration with Brain Iron Accumulation (NBIA) is a heterogeneous group of progressive neurodegenerative diseases characterized by iron deposition in the globus pallidus and the substantia nigra. As of today, 15 distinct monogenetic disease entities have been identified. The four most common forms are pantothenate kinase-associated neurodegeneration (PKAN), phospholipase A2 group VI (PLA2G6)-associated neurodegeneration (PLAN), beta-propeller protein-associated neurodegeneration (BPAN) and mitochondrial membrane protein-associated neurodegeneration (MPAN). Neurodegeneration with Brain Iron Accumulation disorders present with a wide spectrum of clinical symptoms such as movement disorder signs (dystonia, parkinsonism, chorea), pyramidal involvement (e.g., spasticity), speech disorders, cognitive decline, psychomotor retardation, and ocular abnormalities. Treatment remains largely symptomatic but new drugs are in the pipeline. In this review, we discuss the rationale of new compounds, summarize results from clinical trials, provide an overview of important results in cell lines and animal models and discuss the future development of disease-modifying therapies for NBIA disorders. A general mechanistic approach for treatment of NBIA disorders is with iron chelators which bind and remove iron. Few studies investigated the effect of deferiprone in PKAN, including a recent placebo-controlled double-blind multicenter trial, demonstrating radiological improvement with reduction of iron load in the basal ganglia and a trend to slowing of disease progression. Disease-modifying strategies address the specific metabolic pathways of the affected enzyme. Such tailor-made approaches include provision of an alternative substrate (e.g., fosmetpantotenate or 4'-phosphopantetheine for PKAN) in order to bypass the defective enzyme. A recent randomized controlled trial of fosmetpantotenate, however, did not show any significant benefit of the drug as compared to placebo, leading to early termination of the trials' extension phase. 4'-phosphopantetheine showed promising results in animal models and a clinical study in patients is currently underway. Another approach is the activation of other enzyme isoforms using small molecules (e.g., PZ-2891 in PKAN). There are also compounds which counteract downstream cellular effects. For example, deuterated polyunsaturated fatty acids (D-PUFA) may reduce mitochondrial lipid peroxidation in PLAN. In infantile neuroaxonal dystrophy (a subtype of PLAN), desipramine may be repurposed as it blocks ceramide accumulation. Gene replacement therapy is still in a preclinical stage.

Keywords: BPAN; MPAN; beta-propeller protein-associated neurodegeneration; disease-modification therapies; iron chelating agents; neurodegeneration with brain iron accumulation; pantothenate kinase-associated neurodegeneration; plan.

Conflict of interest statement

TK served as coordinating investigator of the FORT trial; received research funding from Retrophin, Inc.; served as coordinating investigator of the deferiprone in PKAN randomized and extension trial; received research funding from ApoPharma Inc.; received support from the European Commission 7th Framework Programme (FP7/2007-2013, HEALTHF2-2011; Grant Agreement No. 277984, TIRCON) and from the European Reference Network for Rare Neurological Diseases (ERN-RND), co-funded by the European Commission (ERN-RND: 3HP 767231); provided consulting services to CoA Therapeutics, Comet Therapeutics, and Retrophin, Inc.; received travel support from ApoPharma Inc. SS was supported by the LMU Excellence Initiative, Braun Stiftung, Ara Parseghian Medical Research Foundation, and Stiftung Verum. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Iankova, Karin, Klopstock and Schneider.

References

    1. Orphanet . Neurodegeneration With Brain Iron Accumulation. (2010). Available online at: (accessed November 12, 2020).
    1. Levi S, Tiranti V. Neurodegeneration with brain iron accumulation disorders: valuable models aimed at understanding the pathogenesis of iron deposition. Pharmaceuticals (Basel). (2019) 12:27. 10.3390/ph12010027
    1. Puig S, Ramos-Alonso L, Romero AM, Martinez-Pastor M. The elemental role of iron in DNA synthesis and repair. Metallomics. (2017) 9:1483. 10.1039/c7mt00116a
    1. Xu J, Jia Z, Knutson MD, Leeuwenburgh C. Impaired iron status in aging research. Int J Mol Sci. (2012) 13:2368–86. 10.3390/ijms13022368
    1. Ward RJ, Zucca FA, Duyn JH, Crichton RR, Zecca L. The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol. (2014) 13:1045–60. 10.1016/S1474-4422(14)70117-6
    1. Roberts BR, Ryan TM, Bush AI, Masters CL, Duce JA. The role of metallobiology and amyloid-β peptides in Alzheimer's disease. J Neurochem. (2012) 120(Suppl. 1):149–66. 10.1111/j.1471-4159.2011.07500.x
    1. Dusek P, Schneider SA, Aaseth J. Iron chelation in the treatment of neurodegenerative diseases. J Trace Elem Med Biol. (2016) 38:81–92. 10.1016/j.jtemb.2016.03.010
    1. Drecourt A, Babdor J, Dussiot M, Petit F, Goudin N, Garfa-Traoré M, et al. . Impaired transferrin receptor palmitoylation and recycling in neurodegeneration with brain iron accumulation. Am J Hum Genet. (2018) 102:266–77. 10.1016/j.ajhg.2018.01.003
    1. Kwiatkowski JL, Cohen AR. Iron chelation therapy in sickle-cell disease and other transfusion-dependent anemias. Hematol Oncol Clin North Am. (2004) 18:1355–77, ix. 10.1016/j.hoc.2004.06.019
    1. Cohen AR. New advances in iron chelation therapy. Hematology Am Soc Hematol Educ Program. (2006) 42–7. 10.1182/asheducation-2006.1.42
    1. Finkenstedt A, Wolf E, Höfner E, Gasser BI, Bosch S, Bakry R, et al. . Hepatic but not brain iron is rapidly chelated by deferasirox in aceruloplasminemia due to a novel gene mutation. J Hepatol. (2010) 53:1101–7. 10.1016/j.jhep.2010.04.039
    1. Fredenburg AM, Sethi RK, Allen DD, Yokel RA. The pharmacokinetics and blood-brain barrier permeation of the chelators 1,2 dimethly-, 1,2 diethyl-, and 1-[ethan-1'ol]-2-methyl-3-hydroxypyridin-4-one in the rat. Toxicology. (1996) 108:191–9. 10.1016/0300-483x(95)03301-u
    1. Habgood MD, Liu ZD, Dehkordi LS, Khodr HH, Abbott J, Hider RC. Investigation into the correlation between the structure of hydroxypyridinones and blood-brain barrier permeability. Biochem Pharmacol. (1999) 57:1305–10. 10.1016/s0006-2952(99)00031-3
    1. Hamilton KO, Stallibrass L, Hassan I, Jin Y, Halleux C, Mackay M. The transport of two iron chelators, desferrioxamine B and L1, across Caco-2 monolayers. Br J Haematol. (1994) 86:851–7. 10.1111/j.1365-2141.1994.tb04841.x
    1. Gallyas F, Környey S. Weiterer Beitrag zur Kenntnis der Hallervorden-Spatzschen Krankheit [A further contribution to the knowledge of the Hallervorden-Spatz disease]. Arch Psychiatr Nervenkr. (1968) 212:33–45. 10.1007/BF00341968
    1. Zorzi G, Zibordi F, Chiapparini L, Bertini E, Russo L, Piga A, et al. . Iron-related MRI images in patients with pantothenate kinase-associated neurodegeneration (PKAN) treated with deferiprone: results of a phase II pilot trial. Mov Disord. (2011) 26:1756–9. 10.1002/mds.23751
    1. Cossu G, Abbruzzese G, Matta G, Murgia D, Melis M, Ricchi V, et al. . Efficacy and safety of deferiprone for the treatment of pantothenate kinase-associated neurodegeneration (PKAN) and neurodegeneration with brain iron accumulation (NBIA): results from a four years follow-up. Parkinsonism Relat Disord. (2014) 20:651–4. 10.1016/j.parkreldis.2014.03.002
    1. Klopstock T, Tricta F, Neumayr L, Karin I, Zorzi G, Fradette C, et al. . Safety and efficacy of deferiprone for pantothenate kinase-associated neurodegeneration: a randomised, double-blind, controlled trial and an open-label extension study. Lancet Neurol. (2019) 18:631–42. 10.1016/S1474-4422(19)30142-5
    1. Fonderico M, Laudisi M, Andreasi NG, Bigoni S, Lamperti C, Panteghini C, et al. . Patient affected by beta-propeller protein-associated neurodegeneration: a therapeutic attempt with iron chelation therapy. Front Neurol. (2017) 8:385. 10.3389/fneur.2017.00385
    1. Lim SY, Tan AH, Ahmad-Annuar A, Schneider SA, Bee PC, Lim JL, et al. . A patient with beta-propeller protein-associated neurodegeneration: treatment with iron chelation therapy. J Mov Disord. (2018) 11:89–92. 10.14802/jmd.17082
    1. Löbel U, Schweser F, Nickel M, Deistung A, Grosse R, Hagel C, et al. . Brain iron quantification by MRI in mitochondrial membrane protein-associated neurodegeneration under iron-chelating therapy. Ann Clin Transl Neurol. (2014) 1:1041–6. 10.1002/acn3.116
    1. Gore E, Appleby BS, Cohen ML, DeBrosse SD, Leverenz JB, Miller BL, et al. . Clinical and imaging characteristics of late onset mitochondrial membrane protein-associated neurodegeneration (MPAN). Neurocase. (2016) 22:476–83. 10.1080/13554794.2016.1247458
    1. Praschberger M, Minkley M, Jackson A, Smith D, Borchers C, Vichinsky E, et al. . Using proteomics to assess potential biomarkers of systemic iron trafficking, inflammation and oxidative stress in a patient with PLA2G6 associated neurodegeneration (PLAN) being treated with deferiprone. Mov Disord. (2014) 29:27. 10.1002/mds.25914
    1. Chinnery PF, Crompton DE, Birchall D, Jackson MJ, Coulthard A, Lombès A, et al. . Clinical features and natural history of neuroferritinopathy caused by the FTL1 460InsA mutation. Brain. (2007) 130:110–9. 10.1093/brain/awl319
    1. Ondrejkovičová M, DraŽilová S, Drakulová M, Siles JL, Zemjarová Mezenská R, Jungová P, et al. . New mutation of the ceruloplasmin gene in the case of a neurologically asymptomatic patient with microcytic anaemia, obesity and supposed Wilson's disease. BMC Gastroenterol. (2020) 20:95. 10.1186/s12876-020-01237-8
    1. Miyake Z, Nakamagoe K, Yoshida K, Kondo T, Tamaoka A. Deferasirox might be effective for microcytic anemia and neurological symptoms associated with aceruloplasminemia: a case report and review of the literature. Intern Med. (2020) 59:1755–61. 10.2169/internalmedicine.4178-19
    1. Van Gelder M, Moris W, Rombout-Sestrienkova E, Van Deursen C, Koek G. Erytrocytapheresis in aceruloplasminemia prevents progression of cerebral iron accumulation after chelator-induced normalization of iron stores. HemaSphere. (2019) 3:592. 10.1097/01.HS9.0000563464.25528.31
    1. Hayashida M, Hashioka S, Miki H, Nagahama M, Wake R, Miyaoka T, et al. . Aceruloplasminemia with psychomotor excitement and neurological sign was improved by minocycline (case report). Medicine (Baltimore). (2016) 95:e3594. 10.1097/MD.0000000000003594
    1. Skidmore FM, Drago V, Foster P, Schmalfuss IM, Heilman KM, Streiff RR. Aceruloplasminaemia with progressive atrophy without brain iron overload: treatment with oral chelation. J Neurol Neurosurg Psychiatry. (2008) 79:467–70. 10.1136/jnnp.2007.120568
    1. Tai M, Matsuhashi N, Ichii O, Suzuki T, Ejiri Y, Kono S, et al. . Case of presymptomatic aceruloplasminemia treated with deferasirox. Hepatol Res. (2014) 44:1253–8. 10.1111/hepr.12292
    1. Roberti Mdo R, Borges Filho HM, Gonçalves CH, Lima FL. Aceruloplasminemia: a rare disease—diagnosis and treatment of two cases. Rev Bras Hematol Hemoter. (2011) 33:389–92. 10.5581/1516-8484.20110104
    1. Bethlehem C, van Harten B, Hoogendoorn M. Central nervous system involvement in a rare genetic iron overload disorder. Neth J Med. (2010) 68:316–8.
    1. Suzuki Y, Yoshida K, Aburakawa Y, Kuroda K, Kimura T, Terada T, et al. . Effectiveness of oral iron chelator treatment with deferasirox in an aceruloplasminemia patient with a novel ceruloplasmin gene mutation. Intern Med. (2013) 52:1527–30. 10.2169/internalmedicine.52.0102
    1. Rusticeanu M, Zimmer V, Schleithoff L, Wonney K, Viera J, Zimmer A, et al. . Novel ceruloplasmin mutation causing aceruloplasminemia with hepatic iron overload and diabetes without neurological symptoms. Clin Genet. (2014) 85:300–1. 10.1111/cge.12145
    1. Lindner U, Schuppan D, Schleithoff L, Habeck JO, Grodde T, Kirchhof K, et al. . Aceruloplasminaemia: a family with a novel mutation and long-term therapy with deferasirox. Horm Metab Res. (2015) 47:303–8. 10.1055/s-0034-1383650
    1. Doyle A, Rusli F, Bhathal P. Aceruloplasminaemia: a rare but important cause of iron overload. BMJ Case Rep. (2015) 2015:bcr2014207541. 10.1136/bcr-2014-207541
    1. Pelucchi S, Mariani R, Ravasi G, Pelloni I, Marano M, Tremolizzo L, et al. . Phenotypic heterogeneity in seven Italian cases of aceruloplasminemia. Parkinsonism Relat Disord. (2018) 51:36–42. 10.1016/j.parkreldis.2018.02.036
    1. Pelucchi S, Pelloni I, Arosio C, Mariani R, Piperno A. Does aceruloplasminemia modulate iron phenotype in thalassemia intermedia? Blood Cells Mol Dis. (2016) 57:112–4. 10.1016/j.bcmd.2015.12.011
    1. Miyajima H, Takahashi Y, Kamata T, Shimizu H, Sakai N, Gitlin JD. Use of desferrioxamine in the treatment of aceruloplasminemia. Ann Neurol. (1997) 41:404–7. 10.1002/ana.410410318
    1. Yonekawa M, Okabe T, Asamoto Y, Ohta M. A case of hereditary ceruloplasmin deficiency with iron deposition in the brain associated with chorea, dementia, diabetes mellitus and retinal pigmentation: administration of fresh-frozen human plasma. Eur Neurol. (1999) 42:157–62. 10.1159/000008091
    1. Loréal O, Turlin B, Pigeon C, Moisan A, Ropert M, Morice P, et al. . Aceruloplasminemia: new clinical, pathophysiological and therapeutic insights. J Hepatol. (2002) 36:851–6. 10.1016/s0168-8278(02)00042-9
    1. Haemers I, Kono S, Goldman S, Gitlin JD, Pandolfo M. Clinical, molecular, and PET study of a case of aceruloplasminaemia presenting with focal cranial dyskinesia. J Neurol Neurosurg Psychiatry. (2004) 75:334–7. 10.1136/jnnp.2003.017434
    1. Hida A, Kowa H, Iwata A, Tanaka M, Kwak S, Tsuji S. Aceruloplasminemia in a Japanese woman with a novel mutation of CP gene: clinical presentations and analysis of genetic and molecular pathogenesis. J Neurol Sci. (2010) 298:136–9. 10.1016/j.jns.2010.08.019
    1. Pan PL, Tang HH, Chen Q, Song W, Shang HF. Desferrioxamine treatment of aceruloplasminemia: long-term follow-up. Mov Disord. (2011) 26:2142–4. 10.1002/mds.23797
    1. Fasano A, Colosimo C, Miyajima H, Tonali PA, Re TJ, Bentivoglio AR. Aceruloplasminemia: a novel mutation in a family with marked phenotypic variability. Mov Disord. (2008) 23:751–5. 10.1002/mds.21938
    1. Mariani R, Arosio C, Pelucchi S, Grisoli M, Piga A, Trombini P, et al. . Iron chelation therapy in aceruloplasminaemia: study of a patient with a novel missense mutation. Gut. (2004) 53:756–8. 10.1136/gut.2003.030429
    1. Bove F, Fasano A. Iron chelation therapy to prevent the manifestations of aceruloplasminemia. Neurology. (2015) 85:1085–6. 10.1212/WNL.0000000000001956
    1. Poli L, Alberici A, Buzzi P, Marchina E, Lanari A, Arosio C, et al. . Is aceruloplasminemia treatable? Combining iron chelation and fresh-frozen plasma treatment. Neurol Sci. (2017) 38:357–60. 10.1007/s10072-016-2756-x
    1. Calder GL, Lee MH, Sachithanandan N, Bell S, Zeimer H, MacIsaac RJ. Aceruloplasminaemia: a disorder of diabetes and neurodegeneration. Intern Med J. (2017) 47:115–8. 10.1111/imj.13309
    1. Kuhn J, Bewermeyer H, Miyajima H, Takahashi Y, Kuhn KF, Hoogenraad TU. Treatment of symptomatic heterozygous aceruloplasminemia with oral zinc sulphate. Brain Dev. (2007) 29:450–3. 10.1016/j.braindev.2007.01.001
    1. Logan JI, Harveyson KB, Wisdom GB, Hughes AE, Archbold GP. Hereditary caeruloplasmin deficiency, dementia and diabetes mellitus. QJM. (1994) 87:663–70.
    1. Hellman NE, Schaefer M, Gehrke S, Stegen P, Hoffman WJ, Gitlin JD, et al. . Hepatic iron overload in aceruloplasminaemia. Gut. (2000) 47:858–60. 10.1136/gut.47.6.858
    1. Badat M, Kaya B, Telfer P. Combination-therapy with concurrent deferoxamine and deferiprone is effective in treating resistant cardiac iron-loading in aceruloplasminaemia. Br J Haematol. (2015) 171:430–2. 10.1111/bjh.13401
    1. Morita H, Ikeda S, Yamamoto K, Morita S, Yoshida K, Nomoto S, et al. . Hereditary ceruloplasmin deficiency with hemosiderosis: a clinicopathological study of a Japanese family. Ann Neurol. (1995) 37:646–56. 10.1002/ana.410370515
    1. Kaneko K, Yoshida K, Arima K, Ohara S, Miyajima H, Kato T, et al. . Astrocytic deformity and globular structures are characteristic of the brains of patients with aceruloplasminemia. J Neuropathol Exp Neurol. (2002) 61:1069–77. 10.1093/jnen/61.12.1069
    1. Brugger F, Kägi G, Pandolfo M, Mencacci NE, Batla A, Wiethoff S, et al. . Neurodegeneration with brain iron accumulation (NBIA) syndromes presenting with late-onset craniocervical dystonia: an illustrative case series. Mov Disord Clin Pract. (2016) 4:254–7. 10.1002/mdc3.12393
    1. Pérez-Aguilar F, Burguera JA, Benlloch S, Berenguer M, Rayón JM. Aceruloplasminemia in an asymptomatic patient with a new mutation. Diagnosis and family genetic analysis. J Hepatol. (2005) 42:947–9. 10.1016/j.jhep.2005.02.013
    1. Ogimoto M, Anzai K, Takenoshita H, Kogawa K, Akehi Y, Yoshida R, et al. . Criteria for early identification of aceruloplasminemia. Intern Med. (2011) 50:1415–8. 10.2169/internalmedicine.50.5108
    1. Matsushima A, Yoshida T, Yoshida K, Ohara S, Toyoshima Y, Kakita A, et al. . Superficial siderosis associated with aceruloplasminemia. Case report. J Neurol Sci. (2014) 339:231–4. 10.1016/j.jns.2014.02.014
    1. Riboldi GM, Anstett K, Jain R, Lau H, Swope D. Aceruloplasminemia and putaminal cavitation. Parkinsonism Relat Disord. (2018) 51:121–3. 10.1016/j.parkreldis.2018.03.003
    1. Bjørk MH, Gjerde IO, Tzoulis C, Ulvik RJ, Bindoff LA. A man in his 50s with high ferritin levels and increasing cognitive impairment. Tidsskr Nor Laegeforen. (2015) 135:1369–72. 10.4045/tidsskr.14.1115
    1. Watanabe M, Ohyama K, Suzuki M, Nosaki Y, Hara T, Iwai K, et al. . Aceruloplasminemia with abnormal compound heterozygous mutations developed neurological dysfunction during phlebotomy therapy. Intern Med. (2018) 57:2713–8. 10.2169/internalmedicine.9855-17
    1. Hines MC, Jr, Bonkovsky HL, Rudnick SR, Mhoon JT. Peripheral neuropathy and the ceruloplasmin gene. Ann Intern Med. (2018) 168:894–5. 10.7326/L17-0621
    1. Vroegindeweij LH, van der Beek EH, Boon AJ, Hoogendoorn M, Kievit JA, Wilson JH, et al. . Aceruloplasminemia presents as type 1 diabetes in non-obese adults: a detailed case series. Diabet Med. (2015) 32:993–1000. 10.1111/dme.12712
    1. Vroegindeweij LHP, Langendonk JG, Langeveld M, Hoogendoorn M, Kievit AJA, Di Raimondo D, et al. . New insights in the neurological phenotype of aceruloplasminemia in Caucasian patients. Parkinsonism Relat Disord. (2017) 36:33–40. 10.1016/j.parkreldis.2016.12.010
    1. Vroegindeweij LHP, Boon AJW, Wilson JHP, Langendonk JG. Effects of iron chelation therapy on the clinical course of aceruloplasminemia: an analysis of aggregated case reports. Orphanet J Rare Dis. (2020) 15:105. 10.1186/s13023-020-01385-w
    1. World Health Organization . Overview of Malaria Treatment. (2018). Available online at: (accessed November 12, 2020).
    1. Zhang Y, Xu G, Zhang S, Wang D, Saravana Prabha P, Zuo Z. Antitumor research on artemisinin and its bioactive derivatives. Nat Prod Bioprospect. (2018) 8:303–19. 10.1007/s13659-018-0162-1
    1. Våtsveen TK, Myhre MR, Steen CB, Wälchli S, Lingjærde OC, Bai B, et al. . Artesunate shows potent anti-tumor activity in B-cell lymphoma. J Hematol Oncol. (2018) 11:23. 10.1186/s13045-018-0561-0
    1. Zheng L, Pan J. The anti-malarial drug artesunate blocks Wnt/β-catenin pathway and inhibits growth, migration and invasion of uveal melanoma cells. Curr Cancer Drug Targets. (2018) 18:988–98. 10.2174/1568009618666180425142653
    1. Das AK. Anticancer effect of antimalarial artemisinin compounds. Ann Med Health Sci Res. (2015) 5:93–102. 10.4103/2141-9248.153609
    1. Ba Q, Zhou N, Duan J, Chen T, Hao M, Yang X, et al. . Dihydroartemisinin exerts its anticancer activity through depleting cellular iron via transferrin receptor-1. PLoS ONE. (2012) 7:e42703. 10.1371/journal.pone.0042703
    1. Lu JJ, Chen SM, Zhang XW, Ding J, Meng LH. The anti-cancer activity of dihydroartemisinin is associated with induction of iron-dependent endoplasmic reticulum stress in colorectal carcinoma HCT116 cells. Invest New Drugs. (2011) 29:1276–83. 10.1007/s10637-010-9481-8
    1. Hogarth P. Neurodegeneration with brain iron accumulation: diagnosis and management. J Mov Disord. (2015) 8:1–13. 10.14802/jmd.14034
    1. Hayflick SJ, Westaway SK, Levinson B, Zhou B, Johnson MA, Ching KH, et al. . Genetic, clinical, and radiographic delineation of Hallervorden-Spatz syndrome. N Engl J Med. (2003) 348:33–40. 10.1056/NEJMoa020817
    1. Orellana DI, Santambrogio P, Rubio A, Yekhlef L, Cancellieri C, Dusi S, et al. . Coenzyme A corrects pathological defects in human neurons of PANK2-associated neurodegeneration. EMBO Mol Med. (2016) 8:1197–211. 10.15252/emmm.201606391
    1. Srinivasan B, Baratashvili M, van der Zwaag M, Kanon B, Colombelli C, Lambrechts RA, et al. . Extracellular 4'-phosphopantetheine is a source for intracellular coenzyme A synthesis. Nat Chem Biol. (2015) 11:784–92. 10.1038/nchembio.1906
    1. Rana A, Seinen E, Siudeja K, Muntendam R, Srinivasan B, van der Want JJ, et al. . Pantethine rescues a Drosophila model for pantothenate kinase-associated neurodegeneration. Proc Natl Acad Sci USA. (2010) 107:6988–93. 10.1073/pnas.0912105107
    1. Álvarez-Córdoba M, Fernández Khoury A, Villanueva-Paz M, Gómez-Navarro C, Villalón-García I, Suárez-Rivero JM, et al. . Pantothenate rescues iron accumulation in pantothenate kinase-associated neurodegeneration depending on the type of mutation. Mol Neurobiol. (2019) 56:3638–56. 10.1007/s12035-018-1333-0
    1. Jeong SY, Hogarth P, Placzek A, Gregory AM, Fox R, Zhen D, et al. . 4′-Phosphopantetheine corrects CoA, iron, and dopamine metabolic defects in mammalian models of PKAN. EMBO Mol Med. (2019) 11:e10489. 10.15252/emmm.201910489
    1. Orrell RW. Hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration (HARP syndrome). In: Kompoliti K, Verhagen L, editors. Encyclopedia of Movement Disorders. 1st ed. Academic Press; (2010). p. 59–61.
    1. Balibar CJ, Hollis-Symynkywicz MF, Tao J. Pantethine rescues phosphopantothenoylcysteine synthetase and phosphopantothenoylcysteine decarboxylase deficiency in Escherichia coli but not in Pseudomonas aeruginosa. J Bacteriol. (2011) 193:3304–12. 10.1128/JB.00334-11
    1. Elbaum D, Beconi MG, Monteagudo E, Di Marco A, Quinton MS, Lyons KA, et al. . Fosmetpantotenate (RE-024), a phosphopantothenate replacement therapy for pantothenate kinase-associated neurodegeneration: mechanism of action and efficacy in nonclinical models. PLoS ONE. (2018) 13:e0192028. 10.1371/journal.pone.0192028
    1. Christou YP, Tanteles GA, Kkolou E, Ormiston A, Konstantopoulos K, Beconi M, et al. . Open-label fosmetpantotenate, a phosphopantothenate replacement therapy in a single patient with atypical PKAN. Case Rep Neurol Med. (2017) 2017:3247034. 10.1155/2017/3247034
    1. Roa P, Stoeter P, Perez-Then E, Santana M. A pilot study of a potential phosphopantothenate replacement therapy in 2 patients with pantothenate kinase-associated neurodegeneration. Int J Rare Dis Orphan Drugs. (2017) 2:1006.
    1. Klopstock T, Escolar ML, Marshall RD, Perez-Dueñas B, Tuller S, Videnovic A, et al. . The fosmetpantotenate replacement therapy (FORT) randomized, double-blind, placebo-controlled pivotal trial: study design and development methodology of a novel primary efficacy outcome in patients with pantothenate kinase-associated neurodegeneration. Clin Trials. (2019) 16:410–8. 10.1177/1740774519845673
    1. Klopstock T, Videnovic A, Bischoff AT, Bonnet C, Cif L, Comella C, et al. . Fosmetpantotenate randomized controlled trial in pantothenate kinase associated neurodegeneration. Mov Disord. (2020). 10.1002/mds.28392. [Epub ahead of print].
    1. Retrophin . Retrophin Announces Topline Results from Phase 3 FORT Study of Fosmetpantotenate in Patients with PKAN. (2019). Available online at: (accessed November 12, 2020).
    1. 7th International Symposium on NBIA & Related Disorders. Update on the CoA-Z Clinical Trial. (2020). Available online at: (accessed November 12, 2020).
    1. Brunetti D, Dusi S, Giordano C, Lamperti C, Morbin M, Fugnanesi V, et al. . Pantethine treatment is effective in recovering the disease phenotype induced by ketogenic diet in a pantothenate kinase-associated neurodegeneration mouse model. Brain. (2014) 137:57–68. 10.1093/brain/awt325
    1. Di Meo I, Colombelli C, Srinivasan B, de Villiers M, Hamada J, Jeong SY, et al. . Acetyl-4′-phosphopantetheine is stable in serum and prevents phenotypes induced by pantothenate kinase deficiency. Sci Rep. (2017) 7:11260. 10.1038/s41598-017-11564-8
    1. Chang X, Zhang J, Jiang Y, Yao B, Wang J, Wu Y. Pilot trial on the efficacy and safety of pantethine in children with pantothenate kinase-associated neurodegeneration: a single-arm, open-label study. Orphanet J Rare Dis. (2020) 15:248. 10.1186/s13023-020-01530-5
    1. Sharma LK, Subramanian C, Yun MK, Frank MW, White SW, Rock CO, et al. . A therapeutic approach to pantothenate kinase associated neurodegeneration. Nat Commun. (2018) 9:4399. 10.1038/s41467-018-06703-2
    1. Yale School of Medicine . Choukri Ben Mamoun, PhD, Wins Best Presentation in Yale Lifesciences Pitchfest 2020. (2021). Available online at: (accessed February 11, 2021).
    1. 7th International Symposium on NBIA & Related Disorders. Status of PKAN Gene Therapy. (2020). Available online at: (accessed November 12, 2020).
    1. Burke JE, Dennis EA. Phospholipase A2 biochemistry. Cardiovasc Drugs Ther. (2009) 23:49–59. 10.1007/s10557-008-6132-9
    1. Kinghorn KJ, Castillo-Quan JI. Mitochondrial dysfunction and defects in lipid homeostasis as therapeutic targets in neurodegeneration with brain iron accumulation. Rare Dis. (2016) 4:e1128616. 10.1080/21675511.2015.1128616
    1. Mori A, Hatano T, Inoshita T, Shiba-Fukushima K, Koinuma T, Meng H, et al. . Parkinson's disease-associated iPLA2-VIA/PLA2G6 regulates neuronal functions and α-synuclein stability through membrane remodeling. Proc Natl Acad Sci USA. (2019) 116:20689–99. 10.1073/pnas.1902958116
    1. Guo YP, Tang BS, Guo JF. PLA2G6-Associated Neurodegeneration (PLAN): review of clinical phenotypes and genotypes. Front Neurol. (2018) 9:1100. 10.3389/fneur.2018.01100
    1. Walkley SU, Baker HJ, Rattazzi MC, Haskins ME, Wu JY. Neuroaxonal dystrophy in neuronal storage disorders: evidence for major GABAergic neuron involvement. J Neurol Sci. (1991) 104:1–8. 10.1016/0022-510x(91)90208-o
    1. Altuame FD, Foskett G, Atwal PS, Endemann S, Midei M, Milner P, et al. . The natural history of infantile neuroaxonal dystrophy. Orphanet J Rare Dis. (2020) 15:109. 10.1186/s13023-020-01355-2
    1. Gregory A, Westaway SK, Holm IE, Kotzbauer PT, Hogarth P, Sonek S, et al. . Neurodegeneration associated with genetic defects in phospholipase A(2). Neurology. (2008) 71:1402–9. 10.1212/01.wnl.0000327094.67726.28
    1. Gregory A, Kurian MA, Maher ER, Hogarth P, Hayflick SJ. PLA2G6-associated neurodegeneration. 2008 Jun 19 [Updated 2017 Mar 23]. In: Adam MP, Ardinger HH, Pagon RA, et al.., editors. GeneReviews®. Seattle, WA: University of Washington; (1993–2020).
    1. Repetto M, Semprine J, Boveris A. Lipid peroxidation: chemical mechanism, biological implications and analytical determination. In: Catala A, editor. Lipid Peroxidation. IntechOpen; (2012). Available online at: (accessed November 12, 2020).
    1. Beaudoin-Chabot C, Wang L, Smarun AV, Vidović D, Shchepinov MS, Thibault G. Deuterated polyunsaturated fatty acids reduce oxidative stress and extend the lifespan of C. elegans. Front Physiol. (2019) 10:641. 10.3389/fphys.2019.00641
    1. Zesiewicz T, Heerinckx F, De Jager R, Omidvar O, Kilpatrick M, Shaw J, et al. . Randomized, clinical trial of RT001: early signals of efficacy in Friedreich's ataxia. Mov Disord. (2018) 33:1000–5. 10.1002/mds.27353
    1. Adams D, Dastgir J, Flora C, Molinari RJ, Heerinckx F, Milner PG, et al. . Case Report: Expanded Access Treatment of an Infantile Neuroaxonal Dystrophy (INAD) Patient with a Novel, Stabilized Polyunsaturated Fatty Acid Drug. Poster. Available online at: (accessed November 12, 2020).
    1. Adams D, Midei M, Dastgir J, Flora C, Molinari RJ, Heerinckx F, et al. . Treatment of Infantile Neuroaxonal Dystrophy with RT001: A di-Deuterated Ethyl Ester of Linoleic Acid: Report of Two Cases. IMD Reports (2020). p. 1–7. 10.1002/jmd2.12116
    1. Clinical Trials . A Study to Assess Efficacy and Safety of RT001 in Subjects With Infantile Neuroaxonal Dystrophy. (2019). Available online at: (accessed November 12, 2020).
    1. 7th International Symposium on NBIA & Related Disorders. Development and Progress of a Treatment Trial for Infantile Neuroaxonal Dystrophy with RT001D. (2020). Available online at: (accessed November 12, 2020).
    1. Lin G, Lee PT, Chen K, Mao D, Tan KL, Zuo Z, et al. . Phospholipase PLA2G6, a parkinsonism-associated gene, affects Vps26 and Vps35, retromer function, and ceramide levels, similar to α-synuclein gain. Cell Metab. (2018) 28:605–18.e6. 10.1016/j.cmet.2018.05.019
    1. Clinical Trials . Desipramine in Infantile Neuroaxonal Dystrophy (INAD). (2018). Available online at: (accessed November 12, 2020)
    1. Whaler S. Novel Therapeutic Strategies in NBIA: A Gene Therapy Approach for PLA2G6-Associated Neurodegeneration (dissertation). London: University College London; (2018).
    1. 7th International Symposium on NBIA & Related Disorders. Therapeutic Approaches to Restore PLA2G6 Enzyme Function in INAD. (2020). Available online at: (accessed November 12, 2020).
    1. Paudel R, Li A, Wiethoff S, Bandopadhyay R, Bhatia K, de Silva R, et al. . Neuropathology of Beta-propeller protein associated neurodegeneration (BPAN): a new tauopathy. Acta Neuropathol Commun. (2015) 3:39. 10.1186/s40478-015-0221-3
    1. Parzych KR, Klionsky DJ. An overview of autophagy: morphology, mechanism, and regulation. Antioxid Redox Signal. (2014) 20:460–73. 10.1089/ars.2013.5371
    1. Saitsu H, Nishimura T, Muramatsu K, Kodera H, Kumada S, Sugai K, et al. . De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood. Nat Genet. (2013) 45:445-9–449e1. 10.1038/ng.2562
    1. Zhao YG, Sun L, Miao G, Ji C, Zhao H, Sun H, et al. . The autophagy gene Wdr45/Wipi4 regulates learning and memory function and axonal homeostasis. Autophagy. (2015) 11:881–90. 10.1080/15548627.2015.1047127
    1. Wan H, Wang Q, Chen X, Zeng Q, Shao Y, Fang H, et al. . WDR45 contributes to neurodegeneration through regulation of ER homeostasis and neuronal death. Autophagy. (2020) 16:531–47. 10.1080/15548627.2019.1630224
    1. Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol. (2011) 13:132–41. 10.1038/ncb2152
    1. Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell. (2017) 168:960–76. 10.1016/j.cell.2017.02.004
    1. Yoo YJ, Kim H, Park SR, Yoon YJ. An overview of rapamycin: from discovery to future perspectives. J Ind Microbiol Biotechnol. (2017) 44:537–53. 10.1007/s10295-016-1834-7
    1. Arriola Apelo SI, Lamming DW. Rapamycin: an InhibiTOR of aging emerges from the soil of Easter Island. J Gerontol A Biol Sci Med Sci. (2016) 71:841–9. 10.1093/gerona/glw090
    1. Bové J, Martínez-Vicente M, Vila M. Fighting neurodegeneration with rapamycin: mechanistic insights. Nat Rev Neurosci. (2011) 12:437–52. 10.1038/nrn3068
    1. resTORbio . resTORbio Announces Initiation of Phase 1b/2a Trial of RTB101 in Parkinson's Disease. (2019). Available online at: (accessed July 20, 2020)
    1. Intrado Globe Newswire . resTORbio Announces Initiation of Phase 1b/2a Trial of RTB101 in Parkinson's Disease. (2019). Available online at: (accessed November 12, 2020).
    1. NBIA Disorders Association . Research Identifies Several Possible Drug Candidates for Treating BPAN. (2020). Available online at: (accessed November 12, 2020).
    1. NBIA Disorders Association . Study Sparks New Approach to BPAN Understanding and Treatment. (2020). Available online at: (accessed November 12, 2020).
    1. Hartig MB, Iuso A, Haack T, Kmiec T, Jurkiewicz E, Heim K, et al. . Absence of an orphan mitochondrial protein, c19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation. Am J Hum Genet. (2011) 89:543–50. 10.1016/j.ajhg.2011.09.007
    1. Venco P, Bonora M, Giorgi C, Papaleo E, Iuso A, Prokisch H, et al. . Mutations of C19orf12, coding for a transmembrane glycine zipper containing mitochondrial protein, cause mis-localization of the protein, inability to respond to oxidative stress and increased mitochondrial Ca2+. Front Genet. (2015) 6:185. 10.3389/fgene.2015.00185
    1. Marchi S, Patergnani S, Pinton P. The endoplasmic reticulum-mitochondria connection: one touch, multiple functions. Biochim Biophys Acta. (2014) 1837:461–9. 10.1016/j.bbabio.2013.10.015
    1. Area-Gomez E, Schon EA. Mitochondria-associated ER membranes and Alzheimer disease. Curr Opin Genet Dev. (2016) 38:90–6. 10.1016/j.gde.2016.04.006
    1. Iuso A, Sibon OC, Gorza M, Heim K, Organisti C, Meitinger T, et al. . Impairment of Drosophila orthologs of the human orphan protein C19orf12 induces bang sensitivity and neurodegeneration. PLoS ONE. (2014) 9:e89439. 10.1371/journal.pone.0089439
    1. Zanardi A, Conti A, Cremonesi M, D'Adamo P, Gilberti E, Apostoli P, et al. . Ceruloplasmin replacement therapy ameliorates neurological symptoms in a preclinical model of aceruloplasminemia. EMBO Mol Med. (2018) 10:91–106. 10.15252/emmm.201708361
    1. Darras BT, Chiriboga CA, Iannaccone ST, Swoboda KJ, Montes J, Mignon L, et al. . Nusinersen in later-onset spinal muscular atrophy: long-term results from the phase 1/2 studies. Neurology. (2019) 92:e2492–506. 10.1212/WNL.0000000000007527
    1. Leavitt BR, Tabrizi SJ. Antisense oligonucleotides for neurodegeneration. Science. (2020) 367:1428–9. 10.1126/science.aba4624
    1. Wan L, Dreyfuss G. Splicing-correcting therapy for SMA. Cell. (2017) 170:5. 10.1016/j.cell.2017.06.028
    1. Day S, Jonker AH, Lau LPL, Hilgers RD, Irony I, Larsson K, et al. . Recommendations for the design of small population clinical trials. Orphanet J Rare Dis. (2018) 13:195. 10.1186/s13023-018-0931-2
    1. Beconi MG, Di Marco A, Monteagudo E, et al. . RE-024, a phosphopantothenate replacement therapy for PKAN: mechanism of action and efficacy in nonclinical models. In: Proceedings of the ACMG Annual Clinical Genetics Meeting, March 2016. Tampa, FL: (2016).

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren