Wolfram syndrome is a rare genetic spectrum disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration, and ranges from mild to severe clinical symptoms. There is currently no treatment to delay, halt, or reverse the progression of Wolfram syndrome, raising the urgency for innovative therapeutics for this disease. Here, we summarize our vision for developing novel treatment strategies and achieving a cure for Wolfram-syndrome-spectrum disorder

Abreu, Damien

Urano, Fumihiko

English

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Washington University School of Medicine Digital Commons@Becker Open Access Publications 10-1-2019 Current landscape of treatments for Wolfram syndrome Damien Abreu Fumihiko Urano Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs Series: Trends in Rare Disease TherapeuticsScience & SocietyCurrent Landscapeof Treatments forWolfram SyndromeDamien Abreu1,2and Fumihiko Urano1,3,*Wolfram syndrome is a rare geneticspectrum disorder characterized by in-sulin-dependent diabetes mellitus, op-tic nerve atrophy, and progressive neu-rodegeneration, and ranges from mildto severe clinical symptoms. There iscurrently no treatment to delay, halt,or reverse the progression of Wolframsyndrome, raising the urgency for inno-vative therapeutics for this disease.Here, we summarize our vision fordeveloping novel treatment strategiesand achieving a cure for Wolfram-syn-drome-spectrum disorder.Clinical Manifestations ofWolfram SyndromeWolfram syndrome is a rare, monogeniclife-threatening disease caused largelyby mutations in the WFS1 gene or, in asmall fraction of patients, pathogenicvariants in the CISD2 gene [1]. While in-sulin-dependent diabetes mellitus, op-tic nerve atrophy, and neurodegenera-tion are cardinal features of thisdisease, many patients also developother symptoms, ranging from hearingloss and endocrine deficiencies toneurological and psychiatric conditions[1]. Accordingly, recent clinical and ge-netic findings have revealed thatWolfram syndrome is best character-ized as a spectrum disorder. MostWolfram syndrome patients carry tworecessive pathogenic variants in theWFS1 gene. The disease begins tomanifest with the clinical onset of insu-lin-dependent diabetes mellitus ataround age 6 years and optic nerve at-rophy at age 10 years. Diabetes insipi-dus, neurogenic bladder, obstructivesleep apnea, and deafness may alsodevelop in the next two decades oflife, along with symptoms of brainstemand cerebellar atrophy, such asdysphagia, ataxia, and central sleep ap-nea [1–4]. Some pathogenic variants ofWFS1, particularly dominant variants,cause deafness or diabetes alone [5,6].Other dominant WFS1 variants giverise to deafness and optic nerve atro-phy or autosomal dominant congenitalcataracts [7,8]. Recently, Dr. Hatters-ley’s team and ours identified severaldominant de novo WFS1 variants asso-ciated with a genetic syndrome ofneonatal/infancy-onset diabetes,congenital sensorineural deafness, andcongenital cataracts [9]. Consequently,WFS1 is a locus of broad interest tovarious disease processes, highlightingthe need for therapeutics targeting thegene towards potential treatments forWolfram-syndrome-spectrumdisorders.Wolfram syndrome is recognized as aprototype of endoplasmic reticulum(ER) disorder [10]. The ER plays a criticalrole in the proper folding of secretoryand membrane proteins, calcium ho-meostasis, and lipid biosynthesis. InWolfram syndrome, dysregulation ofcalcium homeostasis and misfolding ofpathogenic WFS1 variants causes ERstress in pancreatic b cells, neurons,retinal ganglion cells and oligodendro-cytes, resulting in the dysfunction anddegeneration of affected tissues. ERdysfunction can also alter mitochon-drial dynamics, thereby contributing toneuropsychiatric aspects of this disease[11]. Wolfram syndrome is thus a sys-temic disorder caused by ER dysfunc-tion with no treatments available todelay, halt, or reverse disease progres-sion. Nevertheless, numerous avenuesof therapeutic development arecurrently under study, heralding thepossibility of new treatments on the ho-rizon (Figure 1). Below, we discuss theongoing efforts on the developmentof novel treatments for Wolframsyndrome.Chemical ChaperonesA common molecular signature ofWolfram syndrome is cellular stresscaused by the expression of mutantWolfram syndrome 1 (WFS1) proteinsderived from pathogenic WFS1 alleles.To resolve this, we are testing chemicalchaperones that can optimize the struc-ture of mutant WFS1 proteins. Chemi-cal chaperones, such as 4-phenylbutyricacid and tauroursodeoxycholic acid,are drugs that are known to mitigateER stress by rescuing or stabilizing thenative conformation of mutant WFS1proteins, thereby reducing protein ag-gregation and ER stress [12] (Figure 1).Such designer chemical chaperoneshold the potential to delay Wolframsyndrome disease progression byreducing the misfolded WFS1 proteinload in affected cell types, therebysalvaging remaining tissue function.ER Calcium StabilizersTo target calcium dyshomeostasis forthe treatment of Wolfram syndrome,we are developing and repurposing pu-tative ER calcium stabilizers. Werecently discovered, for example, thatdantrolene sodium, a US Food andDrug Administration (FDA)-approveddrug for malignant hyperthermia andmuscle spasm, can act as an ER calciumstabilizer by targeting ER calcium trans-porters, specifically ryanodine recep-tors. Dantrolene sodium can suppresscell death and dysfunction in neuronaland b cell mouse models of Wolframsyndrome, as well as in induced plurip-otent stem cell (iPSC) models of this dis-ease [13] (Figure 1). These resultsprompted us to initiate an ongoingphase 1b/2 clinical trial of dantrolenesodium to assess its safety, tolerability,and efficacy in pediatric and adultTrends in Pharmacological Sciences, October 2019, Vol. 40, No. 10 711Trends in Pharmacological Sciencespatients with Wolfram syndrome (Clin-ical Trial Number: NCT02829268i).We are also now developing novel ERcalcium stabilizers tailored for Wolframtogether with the National Centerfor Advancing Translational Sciences(NCATS)ii. These second-generation ERcalcium stabilizers also target ER calciumtransporters, but are intended to besafer, more potent and have greaterbioavailability to the central nervous sys-tem and eyes than dantrolene sodium.Targeting ER StressAn interestingmolecular target for ther-apeutic development is p21, whichplays a role in cell proliferation and sur-vival after ER stress. Valproic acid, awell-known mood stabilizer, has beenshown to increase the expression ofp21 and confer protection against celldeath in a cell of Wolfram syndrome[14]. Valproic acid also induces WFS1expression and modulates the ER stressresponse [15]. A phase 2 double-blind,placebo-controlled drug repurposingtrial is currently underway to evaluatevalproic acid in patients with Wolframsyndrome (Clinical Trial Number:NCT03717909).Glucagon-like peptide (GLP)-1 receptoragonists are another promising treat-ment for preventing ER-stress-medi-ated cell death in Wolfram syndrome.It has been previously shown that GLP-1 can suppress apoptosis in cell modelsof Wolfram syndrome [13]. Now, datafrom two rodent models of Wolframsyndrome and one patient case reporthave confirmed that GLP-1 receptor ag-onists may improve diabetes inWolfram syndrome [16,17]. Further pre-clinical and clinical studies are neededto assess the broader efficacy of GLP-1 agonists in patients with Wolframsyndrome.Potential Other ApproachesRecent reports indicate that WFS1 lossof function is associated with mitochon-drial dysfunction [11,18]. This likelystems from ER calcium leakage/ERstress causing mitochondrial calciumoverload, which results in aberrant or-ganellar function and decreased ATPproduction. In light of these reports,mitochondrial modulators aimed atrestoring mitochondrial function maymerit further investigation in thecontext of Wolfram syndrome, as theymay be able to delay neurodegenera-tion by reducing neuronal dysfunction.Gene TherapyOne of the approaches to provide acure to Wolframs syndrome could bevia gene therapy. Using adeno-associ-ated viral (AAV) systems, wild-typeWFS1 could be transferred into theretinal ganglion cells of patients withWolfram syndrome (Figure 1) to supple-ment the production of correct proteinin the human body. We also envisionusing CRISPR/CAS9 gene editing tech-nology for replacing pathogenic WFS1Figure 1. Current and Potential Therapeutic Strategies for Wolfram Syndrome.Schematic shows various pathophysiological steps in development of Wolfram syndrome. Thediscussed therapies are shown at the step that they target. Therapies currently in clinical trials andbeing developed preclinically are in solid red and dashed blue boxes, respectively. Abbreviations:AAV, adeno-associated virus; ER, endoplasmic reticulum; GLP-1, glucagon-like peptide 1; iPSC,induced pluripotent stem cell; WFS1, Wolfram syndrome 1.712 Trends in Pharmacological Sciences, October 2019, Vol. 40, No. 10Trends in Pharmacological Sciencesvariants with wild-type WFS1 alleles inWolfram syndrome patients’ iPSCs andthen create iPSC-derived organoids tofurther determine whether thisapproach can be used in combinationwith regenerative cell-replacement ef-forts (discussed below).Regenerative MedicineGiven the deleterious effects of chronicER stress on specific cell types inWolfram syndrome, there is a need forregenerative medicine efforts aimed atreplacing these damaged tissues.More specifically, there is a need for re-placing pancreatic b cells and retinalganglion cells in patients, as defects inthese cell types have the greatestimpact on patients’ quality of life. Tothis end, regenerative therapy optionsusing iPSCs have been developed[19]. iPSCs from patients with Wolframsyndrome and their respective siblingsand/or parents have been generated[13], which could potentially be differ-entiated into neural progenitor cells,retinal ganglion cells, oligodendro-cytes, and pancreatic b cells for thera-peutic testing and molecular investiga-tion. These iPSC-derived cell typesmay one day be used for cell-basedreplacement therapy.In addition to developing cell-replace-ment therapeutic strategies, the regen-erative properties of factors such asmesencephalic astrocyte-derived neu-rotrophic factor (MANF), can be testedon tissues especially sensitive to WFS1loss of function. MANF has been shownto activate proliferation of primary isletsand confer protection against ER-stress-mediated cell death [20]. A ther-apeutic strategy could be to directlydeliver MANF to neurons, pancreatic bcells and retinal ganglion cells via AAVsystems, with the goal of suppressingneurodegeneration and improving bcell mass, glucose tolerance, and visualacuity. Further safety and efficacystudies will be required to optimize de-livery, minimize adverse effects andmaximize therapeutic benefit.Concluding Remarks and FuturePerspectivesWolfram syndrome is a rare genetic dis-order with more than 200 pathogenicvariants reported in association withdisease. Clinical and genetic heteroge-neity, as well as variable expressivity,pose a challenge for designing effec-tive therapies in this population.We should therefore aim to designpersonalized treatments for Wolframsyndrome patients in the future.The first step towards this goal is tostratify patients based on their ge-netics. Genetic testing based on next-generation sequencing (NGS) technol-ogy, including exome and genomesequencing, has the ability to do thisby identifying DNA variants that highlycorrelate with each patient’s clinicalsigns and symptoms. Routine use ofNGS-based genetic testing will notonly facilitate patient counseling bymedical geneticists and genetic coun-selors, but also serve as a first step to-wards designing personalized treat-ments for patients with Wolframsyndrome.Notably, although Wolfram syndromeis an ultra-rare genetic disorder, its con-stituent medical components (e.g., dia-betes mellitus, deafness, and retinaldegeneration) and underlying ER path-ophysiology are not as rare. Conse-quently, novel treatments designed forthis ultra-rare disorder may havebroader implications for more commonmedical conditions related to ER stressand dysfunction. Thus, by leveragingthe tools and therapeutic efforts target-ing Wolfram syndrome, we may iden-tify novel treatment modalities formore prevalent disorders such as dia-betes mellitus and neurodegenerativediseases.AcknowledgmentsThis work was partly supported by thegrants from the National Institutes ofHealth/NIDDK (DK112921, DK113487,DK020579), National Institutes ofHealth/NCATS (TR002065, TR002345),JDRF (2-SRA-2016-233-S-N) and phil-anthropic support from the UnravelWolfram Syndrome Fund, the Silber-man Fund, the Stowe Fund, the SnowFoundation, the Eye Hope Foundation,the Ellie White Foundation for the RareGenetic Disorders, Wolfram SyndromeUK Support Group, French WolframAssociation, and the Feiock Fund toF.U. The authors thank all the mem-bers of the Washington Univer-sity Wolfram Syndrome Study andResearch Clinic for their support (https://wolframsyndrome.dom.wustl.edu) andall the participants in the Wolfram syn-drome International Registry and ClinicalStudy, Research Clinic, and Clinical Trialsfor their time and efforts.Disclaimer StatementF. Urano received research fundingfrom Eli Lilly, Ono Pharmaceutical, andAmarantus BioScience for the develop-ment of MANF-based regenerativetherapy. He also received chemicalcompounds from Amylyx Pharmaceuti-cals, Mitochon Pharmaceuticals, AetasPharma, and National Center forAdvancing Translational Sciences forthe development small molecule-based therapies targeting ER stress.Resourcesiwww.clinicaltrials.goviihttps://ncats.nih.gov/ntu/projects/2017#calcium1Department of Medicine, Division ofEndocrinology, Metabolism, and Lipid Research,Washington University School of Medicine,St. Louis, MO 63110, USA2Medical Scientist Training Program, WashingtonUniversity School of Medicine, St. Louis,MO 63110, USATrends in Pharmacological Sciences, October 2019, Vol. 40, No. 10 713Trends in Pharmacological Sciences3Department of Pathology and Immunology,Washington University School of Medicine,St. Louis, MO 63110, USA*Correspondence:urano@wustl.eduhttps://doi.org/10.1016/j.tips.2019.07.011ª 2019 The Author(s). Published by Elsevier Ltd.This is an open access article under the CC BYlicense (http://creativecommons.org/licenses/by/4.0/).References1. Urano, F. (2016) Wolfram syndrome:diagnosis, management, and treatment.Curr. Diab. Rep. 16, 62. Barrett, T.G. et al. (1995) Neurodegenerationand diabetes: UK nationwide study ofWolfram (DIDMOAD) syndrome. Lancet 346,1458–14633. Hershey, T. et al. (2012) Early brainvulnerability in Wolfram syndrome. PLoSOne 7, e406044. Marshall, B.A. et al. (2013) Phenotypiccharacteristics of early Wolfram syndrome.Orphanet J. Rare Dis. 8, 645. Lesperance, M.M. et al. (2003) Mutationsin the Wolfram syndrome type 1 gene(WFS1) define a clinical entity of dominantlow-frequency sensorineural hearing loss.Arch. Otolaryngol. Head Neck Surg. 129,411–4206. Bonnycastle, L.L. et al. (2013) Autosomaldominant diabetes arising from a wolframsyndrome 1 mutation. Diabetes 62, 3943–39507. Rendtorff, N.D. et al. (2011) Identification ofp.A684V missense mutation in the WFS1gene as a frequent cause of autosomaldominant optic atrophy and hearingimpairment. Am. J. Med. Genet. A 155A,1298–13138. Berry, V. et al. (2013) Wolfram gene (WFS1)mutation causes autosomal dominantcongenital nuclear cataract in humans. Eur.J. Hum. Genet. 21, 1356–13609. De Franco, E. et al. (2017) Dominant ERstress-inducing WFS1 mutations underlie agenetic syndrome of neonatal/infancy-onsetdiabetes, congenital sensorineural deafness,and congenital cataracts. Diabetes 66, 2044–205310. Fonseca, S.G. et al. (2010) Wolframsyndrome 1 gene negatively regulates ERstress signaling in rodent and human cells.J. Clin. Invest. 120, 744–75511. Cagalinec, M. et al. (2016) Roleof mitochondrial dynamics inneuronal development: mechanism forWolfram syndrome. PLoS Biol. 14,e100251112. Shang, L. et al. (2014) b-Cell dysfunction dueto increased ER stress in a stem cell model ofWolfram syndrome. Diabetes 63, 923–93313. Lu, S. et al. (2014) A calcium-dependentprotease as a potential therapeutic target forWolfram syndrome. Proc. Natl. Acad. Sci. U.S. A. 111, E5292–E530114. Gharanei, S. et al. (2013) Vacuolar-type H+-ATPase V1A subunit is a molecular partner ofWolfram syndrome 1 (WFS1) protein, whichregulates its expression and stability. Hum.Mol. Genet. 22, 203–21715. Kakiuchi, C. et al. (2009) Valproate, a moodstabilizer, induces WFS1 expression andmodulates its interaction with ER stressprotein GRP94. PLoS One 4, e413416. Toots, M. et al. (2018) Preventive treatmentwith liraglutide protects againstdevelopment of glucose intolerance in a ratmodel of Wolfram syndrome. Sci. Rep. 8,1018317. Kondo, M. et al. (2018) Activation of GLP-1receptor signalling alleviates cellularstresses and improves beta cell function in amouse model of Wolfram syndrome.Diabetologia 61, 2189–220118. Angebault, C. et al. (2018) ER-mitochondriacross-talk is regulated by the Ca(2+) sensorNCS1 and is impaired in Wolfram syndrome.Sci. Signal. Published online October 23,2018. https://doi.org/10.1126/scisignal.aaq138019. Urano, F. (2014) Wolfram syndrome iPS cells:the first human cell model of endoplasmicreticulum disease. Diabetes 63, 844–84620. Lindahl, M. et al. (2014) MANF isindispensable for the proliferation andsurvival of pancreatic beta cells. Cell Rep. 7,366–375SpotlightInterleukin-13 IsUnlucky for AllergySufferersMarkus M. Xie1and Alexander L. Dent1,*Anaphylaxis, a life-threatening allergicreaction, is dependent on high affinityallergen-specific IgE. Gowthamanet al. now show that a new interleukin(IL)-13-expressing T helper cell subsetspecifically promotes high-affinity IgEresponses. The discovery of T follicularhelper (Tfh)13 cells defines potentialnew targets for allergy therapies.The increase in atopic and allergic dis-eases over the past 30–40 years is ofepidemic proportions and these dis-eases affect millions of people in theUSA [1,2]. Allergic reactions can leadto anaphylaxis, a severe and life-threat-ening form of allergic immuneresponse. Anaphylaxis is a systemic in-flammatory response that results in adramatic loss of blood pressure andcan lead to organ failure. Food al-lergies, especially to peanut proteins,often involve anaphylactic reactions [3].During the priming phase of an allergicimmune reaction, Interleukin-4 (IL-4) isproduced by T helper (Th) cells that pro-mote the production of antigen-specificIgE antibody from B cells. Most IgE thenbinds strongly to Fcε receptors on mastcells. IgE with low affinity for theallergen protein is not sufficient to fullyactivate mast cells and cannot provokeanaphylaxis in the presence of allergen(Figure 1A). However, the interactionof allergen proteins with high-affinityallergen-specific IgE on the mast cellsurface causes crosslinking of the Fcεreceptors, triggering a signalingcascade that leads to mast cell degran-ulation and release of preformed in-flammatory mediators stored in cyto-plasmic granules, including histamine,proteases, cytokines, and chemokines(Figure 1B) [4]. Release of these inflam-matory mediators in a systemicresponse leads to the severe allergic re-action of anaphylaxis.Recent studies have revealed thatspecialized IL-4-secreting T follicularhelper (Tfh) cells are essential for thedevelopment of antigen-specific IgEfrom activated B cells within a cellularstructure found in lymphoid tissuescalled the germinal center [5]. The dis-covery that Tfh cells control IgE re-sponses has expanded our knowledgeof mechanisms that control the devel-opment of allergies. However, a crucialaspect of the anaphylactic response isthat it is dependent on the develop-ment of high-affinity IgE specific forthe allergen [6] and despite the clinicalsignificance of anaphylaxis, the ques-tion of how high-affinity, allergen-spe-cific IgE develops in the germinal centerhas been unclear. Now, investigatorsfrom Yale University and the Jackson714 Trends in Pharmacological Sciences, October 2019, Vol. 40, No. 10Trends in Pharmacological Sciences

Current landscape of treatments for Wolfram syndrome

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Current landscape of treatments for Wolfram syndrome

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