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1、RARE DISEASESImpact,landscape,and possibilitiesCAS INSIGHTSTMRare diseases,or orphan diseases,are a group of disorders that,despite affecting relatively few patients at the individual disease level,collectively affect many worldwide.The World Health Organization(WHO)defines a rare disease as one tha

2、t affects fewer than 65 per 100,000 people;1 however,when combined,would represent approximately 46%of the total worldwide population.13 Due to the rarity of the individual diseases,their complex presentation,and lack of clinician awareness,these conditions are often misdiagnosed or underdiagnosed.4

3、,5 Rare disease treatment and research,such as clinical trial recruitment,is further complicated by small patient populations and underfunding,and as a result,research does not advance as quickly relative to common diseases.1 The term“orphan disease”stems from this unmet need and the perception that

4、 rare diseases have been left“orphaned”by the pharmaceutical industry,with access to specialized healthcare and support made difficult for people living with such conditions.In recent years,awareness of rare diseases has grown,and there have been increased efforts in research to address unmet needs

5、in the field.Most rare diseases are genetic in etiology;consequently,research to identify genetic variants should provide the first steps toward a better understanding of the causes of these conditions.For example,advances in genomic sequencing and precision medicine could improve the diagnosis and

6、targeted treatment of patients with rare diseases.Initiatives and incentives such as the orphan drug legislation have also encouraged pharmaceutical companies to invest more resources in rare disease research.611 This is important because research investment in rare diseases can have positive impact

7、s beyond their small patient populations.Research in rare diseases can lead to breakthroughs in the understanding of more common diseases,such as uncovering shared mechanisms in disease pathophysiology and opening up new treatment pathways for patients.12 An example of this is research around proger

8、in in Hutchinson-Gilford Progeria syndrome(HGPS).HGPS is a rare disease that causes premature aging,and HGPS research may offer insights into common cardiovascular diseases such as heart attacks and strokes.13 This CAS Insights report describes how the CAS Content Collection,the largest human-curate

9、d collection of published scientific information,was instrumental in capturing an overview of the changing landscape of rare diseases.14 Through analysis of the research and publications landscape,we have captured insights into the progress of rare disease medicine,including challenges and potential

10、 opportunities for growth.IntroductionRARE DISEASES REPORT|3Publication and patent landscape:what is on the horizon for rare diseases?Figure 1.Numbers of publications relating to rare diseases from the CAS Content Collection for the period 20032023.Number of publications30,00025,00040,00035,00020,00

11、015,00010,0005,0000202320222021202020192018201720162015201420132012201120102009200820072006200520042003JournalPatentPublication yearThe CAS Content collection currently houses over 530,000 publications about rare diseases,comprised of both journal articles and patents.Analysis of this collection hel

12、ped identify key trends around prominent research institutions,leading journals,and rare diseases currently of high commercial interest.This report will focus on three rare diseases:amyotrophic lateral sclerosis(ALS),Huntingtons disease(HD),and myasthenia gravis(MG).Over the last decade,both journal

13、 and patent publications have been on the rise(Figure 1),with rapid growth in the number of journal publications,particularly between 20192021,whereas the increase in patent publications has been steadier.To identify leading research organizations actively publishing rare disease scientific content,

14、institutions were ranked by publication volume and impact,which was calculated using the average number of citations per publication.Of the leading 15 institutions,67%originated from the United States(including Harvard Medical School),20%from Canada(including the University of British Columbia),and

15、13%from Great Britain(including the University of Oxford).Leading scientific journals for rare diseases were identified using similar methodology,including the New England Journal of Medicine(New Engl J Med),Journal of Clinical Oncology(J Clin Oncol),and Proceedings of the National Academy of Scienc

16、es(Pro Natl Acad Sci USA).Analysis of rare diseases revealed that the highest interest in journal articles was found in HD,15,16 MG,17 ALS,1820 rare tumors and cancers,2127 and systemic lupus erythematosus(SLE).2830 The continual scientific interest stemming from rare diseases means research can lea

17、d to high-impact publications,such as“Targeting huntingtin expression in patients with Huntingtons disease”,31 published in 2019 by researchers in the UK in the New England Journal of Medicine.The article described the results of a Phase I/IIa trial for an oligonucleotide designed by Ionis Pharmaceu

18、ticals and F.HoffmannLa Roche to inhibit messenger ribonucleic acid(mRNA)of HTT,the main gene responsible for HD,and has since been cited over 400 times.Capturing the fieldPatent publication trends also indicate areas of research interest and were analyzed by country/region.The results showed that t

19、he list of top ten patent assignee countries/regions included seven common to both commercial and non-commercial entities(Figure 2).The US is the highest by countries/regions,contributing 31%and 40%to non-commercial and commercial patents,respectively.Figure 2.Leading organizations in the field of r

20、are diseases from assessment of patent publication data from the CAS Content Collection for the period 2003 to 2023.(A)Donut and(B)bar charts showing geographical distribution and leading organizations,respectively.Regions and institutions were separated into non-commercial and commercial categories

21、.Bar colors in the bar charts correspond to countries or regions shown in the donut charts.Countries or regions represented by their standard three-letter codes United States(USA),China(CHN),South Korea(KOR),France(FRA),Germany(DEU),Japan(JPN),Spain(ESP),Denmark(DEN),Italy(ITA),Belgium(BEL),Switzerl

22、and(CHE),Israel(ISR),and United Kingdom(GBR).OthersBELITADENESPJPNDEUFRAKORCHNUSA18%2%17%31%9%9%4%3%3%3%3%Number of patent publications6005008009007004003002001000University of CaliforniaINSERMJohns Hopkins UniversityKISTUnited States Dept.of HealthUniversity of PennysylvaniaChina Pharmaceutical Uni

23、versityUniversity of TexasYale UniversityHarvard UniversityDuke UniversityColumbia UniversityStanford UniversityZhejiang UniversityKRIBBANon-commercial patent assignees(20032023)Commercial patent assignees(20032023)OthersISRDENFRAKORGBRJPNCHEDEUCHNUSA18%2%2%15%40%6%4%4%4%4%3%Number of patent publica

24、tions600100012008004002000MerckNovartisBristol-Myers SquibbJanssenF.Hoffman-La RocheGenentechBoehringer IngelheimPfizerVertex Pharmaceuti-calsAstraZenecaBiogenAmgenSchering-PloughGlaxoSmithKlineNeiroSearchBPatent filing can be a key indicator of the commercialization of promising research.The Univer

25、sity of California is the top non-commercial patent assignee in the rare diseases space and,since 2015,has filed patents for treatments in ALS(WO2023086603,32 WO2022104148),33 HD(WO2022165538A1),34 and MG(WO2018236955,35 WO2018049053).36 Analysis of the patents from the top six commercial companies

26、helped shed further light on the spread of commercial interest across rare diseases.The following diseases were subsequently found to be of high commercial interest to the top six companies:multiple sclerosis,37 SLE,38 scleroderma,39 and HD,as seen by the higher publication volume versus other disea

27、ses.Additionally,kidney cancer,40 thyroid cancer,41 melanoma42 and multiple myeloma,43 all had relevant patents filed by all six commercial companies.However,the number of patent publications indicates that not all rare diseases are being explored to the same extent.Examples of rare diseases with ap

28、parent low commercial interest include iridocyclitis,44 familial Mediterranean fever,45 Rett syndrome46 and pseudoaldosteronism.47 Commercially underexplored rare cancers include nasopharyngeal carcinoma,48 blastic plasmacytoid dendritic cell cancer49 and B-cell prolymphocytic leukemia.50,51 To iden

29、tify the leading rare diseases in terms of published research,analysis of the CAS Content Collection dataset investigated trends in both journal articles and patents categorized by condition.ALS,HD,and MG publication volumes identified them as leading research areas.The evolution of interest in thes

30、e and other rare diseases over the last five years is shown below(Figure 3);HD,ALS,and MG show a clear,steady,and consistent increase in publications.This increase is most evident for MG,with publications nearly doubling in this 5-year period.The patent-to-journal ratio of rare diseases was analyzed

31、;7 out of 14 scored 1,indicating greater commercial than general research interest.Of the leading rare diseases covered in this report,HD and MG had a patent-to-journal ratio of 1,whereas ALS had a patent-to-journal ratio of 0.7,indicating greater interest from the noncommercial community.The increa

32、sed interest in ALS could be attributable to the viral“ice bucket”phenomenon,which may translate to greater commercial interest a few years down the line.Similarly,interest in rare cancers is generally rising,with a broad increase in publications and all selected rare cancers showing clear,consisten

33、t,and rapid increases in publication numbers.Of special note are Kaposis sarcoma52(cancer affecting the lining of blood vessels and lymph nodes),glioblastoma53(cancer of the brain and/or spinal cord),and thyroid cancer41 with publications more than doubling between 2019 and 2022.Rare cancers general

34、ly are of high commercial interest,with 70%having patent-to-journal ratios 1.Commercial interest in rare diseasesARARE DISEASES REPORT|5Our analysis of the metrics of rare disease publications has shown that despite small patient populations,the research community has not forgotten the impact of rar

35、e diseases and continues to focus on these conditions.The trends identified in this report suggest that interest in rare diseases is increasing and will offer more opportunities in the future.Relative growth(%)20405030100Multiple sclerosisSystemic lupus erythematosusSclerodermaHuntingtons diseaseCys

36、tic fbrosisAmyotrophic lateral sclerosisSarcoidosisCreutzfeldt-Jakob diseaseProgressive supranuclear palsyGuillain-Barre syndromeSjgren syndromeMyasthenia gravisGraves diseaseJuvenile rheumatoid arthritis201820192020202120222023Figure 3.Number of publications(journal and patent)for selected leading

37、rare diseases from the CAS Content Collection.HD,ALS,and MG are highlighted in dashed boxes.Data includes patent and journal publications sourced for the period 20182023 in the field of rare diseases.ARARE DISEASES REPORT|7Research efforts continue to improve our understanding of rare diseases,from

38、their root causes and mechanisms,to their application in novel treatment pathways.Myasthenia gravisMG is a rare,chronic,autoimmune neuromuscular disorder characterized by weakness and rapid fatigue of voluntary muscles,5457 In MG,self-production of antibodies against acetylcholine(ACh)receptor(AChR)

39、or muscle-specific kinase are believed to be the main causes of this condition,57,58 triggering the immune system to mistakenly attack receptors on muscle cells,particularly at the neuromuscular junction,and subsequently hindering muscle contraction (Figure 4).5961Behind the scenes:from genetics to

40、the pathogenesis of rare diseasesFigure 4.Pathogenesis of MG schematic,detailing the three effects of antibodies at the neuromuscular junction and their consequent damaging effects.6264 ACh,acetylcholine;AChR,acetylcholine receptor;NMJ,neuromuscular junction.Anti-AChR antibodiesComplement systemAChC

41、)binding of antibodies to AChR can also activate the complement system that leads to damage and dysfunction of the NMJImpaired signal transmission Endplate and postsynaptic membrane destruction,as well as alterations to AChR distributionB)antibodies may cross-link adjacent AChR molecules,internalizi

42、ng and degrading the AChR complex(A)antibodies block the binding sites on the AChRNeuronMuscleAutoantibodies are thought to be produced by the thymus,which may also contribute to the maturation of autoreactive T cells involved in the autoimmune response in MG.Symptoms caused by the autoimmune effect

43、s of MG can vary widely and complicate diagnosis over time.However,the hallmark symptom of MG is muscle weakness,typically worsening with activity and improving with rest.6569Despite not being considered a purely genetic disorder,MG has a complex genetic background.As such,MG is regarded as an autoi

44、mmune disease with genetic predispositions.Certain genetic variations or polymorphisms may predispose an individual to develop MG.Often,these variations are observed in immune system function genes,such as those encoding human leukocyte antigens(HLAs),specifically the HLA-B8 and HLA-DR3 alleles,7076

45、 and HLA alleles within the major histocompatibility complex(MHC)region.77 Environmental triggers likely interact with genetic susceptibility factors to influence individual development of MG.75 Through the analysis of the CAS Content Collection,we have collated four genes that are associated with M

46、G(Figure 5).Treatments for MG,such as acetylcholinesterase inhibitors,immunosuppressants,and corticosteroids,aim to manage symptoms and improve quality of life.However,no cure is currently available.7981Figure 5.Genes associated with MG based on data from the CAS Content Collection.Only genes with a

47、n association score78 of greater than 0.4 and at least ten records are shown.The majority of records were obtained from text mining.Myasthenia gravisGeneAGRN 0.4LRP4 0.4MUSK 0.4TTN 0.4ACHE 0.7ProteinAgrinLow-density lipoprotein(LDL)receptor related protein 4Muscle associated receptor tyrosine kinase

48、(MuSK)TitinAcetylcholinesterase(AChE)RoleAgrin is a protein involved in development of the NMJ;autoantibodies against agrin have been detected in patients with MG.The LRP4 protein is involved in NMJ signaling;autoantibodies against LRP4 have been detected in individuals with MG.MuSK plays a role in

49、NMJ signaling,and can be used to categorize the MuSK-MG disease subtype,which may be associated with worse patient outcome than other subtypes.Titin plays a key role in muscle contraction,and autoantibodies against titin have been reported in MG patients with thymoma.AChE is an enzyme that helps in

50、breakdown and recycling of acetylcholine as a way to terminate cholinergic signaling.AchE has been studied in the context of a number of diseases including Alzheimers and Parkinsons.RARE DISEASES REPORT|9Amyotrophic lateral sclerosisALS(also known as motor neuron disease or Lou Gehrigs disease)is a

51、rare,progressive,neurodegenerative disorder.ALS affects motor neurons in the brain and spinal cord that control voluntary muscle movement,and the resulting dysfunction leads to muscle weakness,atrophy,and paralysis(Figure 6).8287Figure 6.Pathogenesis of ALS schematic,detailing the effects of the con

52、dition on motor neurons and their cellular structure.Glutamate,8890 protein aggregation,9194 mitochondrial dysfunction,9597 and non neuronal cells all play key roles in ALS pathology.98103Illustration courtesy of https:/ molecules324ROS?ROSEnergyProtein aggregatesMotor neuron1 GlutamateOligodendrocy

53、teMicrogliaAstrocyteEnergyNucleusMutationsSOD1,TARDBP,FUS,and C9orf721 Excessive levels of glutamate are observed in the synaptic cleft.This can damage motor neurons,contributing to their degeneration and death.2 Mutations in SOD1,TARDBP(encoding TDP-43),FUS,and C9orF72 may lead proteins to aggregat

54、e and accumulate within motor neurons and surrounding cells.3 In the mitochondria,impaired energy metabolism and increased production of reactive oxygen species impacts motor neuron degeneration.4 Non-neuronal cells such as astrocytes,microglia,and oligodendrocytes play important roles in ALS pathog

55、enesis.ALS,like MG,also has roots in genetics;however,the condition has been hypothesized not to be a single-gene disease but a plethora of overlapping conditions with common characteristics and genetic factors.104,105 As a result,diagnosis is complex,and treating physicians need to consider each in

56、dividuals medical history,neurological examinations,imaging,electromyography,and nerve conduction study results,as well as the possibility of a differential diagnosis against other plausible causes of muscle weakness and motor dysfunction.106,107 The genetic background of ALS is multifaceted,involvi

57、ng both familial and sporadic forms.While most ALS cases occur without a clear family history,possibly due to a combination of genetic susceptibility and environmental factors,approximately 510%of cases have a known genetic component(Figure 7).108113 Significant genetic heterogeneity of ALS leads to

58、 distinct clinical phenotypes that are associated with disease progression.108,114,115RoleMutations in SOD1 are believed to induce protein misfolding,leading to ALS.Mutations in senataxin are thought to affect its function,leading to juvenile ALS-4,which develops in patients before the age of 25 yea

59、rs.Mutations in TDP-43 may affect gene expression,resulting in some pathologies seen in ALS,such as fibril formation and RNA regulation.Mutations may alter optineurins ability to interact with and consequently remove damaged mitochondria.Mutations in Sequestosome 1 may impair removal of misfolded or

60、 aggregated protein,and reduce autophagy.ProteinSuperoxide dismutase 1SenataxinTDP-43Optineurinp62 protein/Sequestosome 1GeneSOD1 1.0SETC 1.0TARDBP 0.9OPTN 0.9SQSTM1 0.9ANG 0.9VAPB 0.9PRPH 0.9CHCHD10 0.9TBK1 0.9NEFH 0.9Amyotrophic lateral sclerosis(ALS)GeneFUS 0.9PRN1 0.9MATR3 0.9UBQLN2 0.9ALS2 0.8P

61、roteinFused in sarcoma(FUS)RNA binding proteinProfilin 1Matrin 3Ubiquilin 2AlsinRoleMutant FUS has reduced ability to bind to a nuclear import receptor,resulting in accumulation of mutant FUS in the cytoplasm.Mutations in profilin 1 may result in its aggregation alongside TDP-43,which may contribute

62、 to ALS-related dysfunctions.Matrin 3 is a DNA/RNA-binding nuclear protein that interacts with TDP-43 and FUS,and may have a role in ALS.Mutant ubiqilin may have reduced capacity for protein degradation through affected interactions with binding partners and other proteins.Some alsin mutations assoc

63、iated with ALS result in expression of forms without crucial domains,reducing the functionality of alsin as a guanine nucleotide exchange factor.RARE DISEASES REPORT|11Figure 7.Genes associated with ALS based on data from the CAS Content Collection.Only genes with an association score greater than 0

64、.6 and at least 10 records are shown here.Color corresponds to association score:yellow(1.0),light green(0.9),orange(0.8),purple(0.7)and aqua(0.6).The nature of the line indicates the association source,with dashed lines indicating a majority of records resulting from text mining.RoleMutations in SO

65、D1 are believed to induce protein misfolding,leading to ALS.Mutations in senataxin are thought to affect its function,leading to juvenile ALS-4,which develops in patients before the age of 25 years.Mutations in TDP-43 may affect gene expression,resulting in some pathologies seen in ALS,such as fibri

66、l formation and RNA regulation.Mutations may alter optineurins ability to interact with and consequently remove damaged mitochondria.Mutations in Sequestosome 1 may impair removal of misfolded or aggregated protein,and reduce autophagy.Angiogen is known for participating in blood vessel formation an

67、d other pathways,and research is ongoing to uncover its complex role in ALS.VAPB interacts with a number of partners;one extensively studied mutation has several proposed mechanisms in ALS.Upregulation of peripherin(thought to be involved in neuronal growth)has been reported to have neurotoxicity in

68、 mouse models.CHCHD10 mutation and overexpression are associated with mitochondrial abnormalities.Mutations are thought to affect the autophagy function of TBK1.Neurofilaments have a role in the regulation of axon diameter and growth,and mutations have been reported in ALS.angiogeninVesicle-associat

69、ed membrane protein(VAMP)-associated protein B and C(VAPB)PeripherinCoiled-coil-helix-coiled-coil-helix domain containing protein 10TANK binding kinase 1Neurofilament heavy chainANG 0.9VAPB 0.9PRPH 0.9CHCHD10 0.9TBK1 0.9NEFH 0.9Amyotrophic lateral sclerosis(ALS)GeneFUS 0.9PRN1 0.9MATR3 0.9UBQLN2 0.9

70、ALS2 0.8FIG4 0.8KIF5A 0.8ERBB4 0.8CCNF 0.7ANXA11 0.7NEK1 0.6Polyphosphoinositide phosphataseKinesin family member 5AErb-b2 receptor tyrosine kinase 4(ErbB4)Cyclin FAnnexin A11NIMA-related kinase 1There is evidence FIG4 mutations could disrupt intracellular trafficking due to excessive vacuoles,thoug

71、h this mutation is still being investigated.It has been demonstrated that a KIF5A mutation disrupts the autoinhibition of kinesin family member 5A,leading to increased mitochondrial transport.ErbB4 interacts with a number of partners;one reported ALS mutation results in reduced autophosphorylation.M

72、utant CCNF causes abnormal ubiquitination and is believed to contribute to ALS.Mutant annexin A11 has been reported to increase formation of insoluble aggregates,disrupt Ca2+homeostasis,and interfere with RNA transport.NIMA-related kinase 1 has a large role in cellular processes,and two main mutatio

73、ns(a loss of function and missense variant)are thought to be associated with ALS.Figure 8.Potential pathogenesis of HD schematic.The CAG repeat in HTT encodes for mHTT,causing aggregation and inclusion bodies.mHTT causes mitochondrial dysfunction,excitotoxicity,dysregulation of axonal transport and

74、synaptic processes,and neuroinflammation.132143 Illustration courtesy of https:/HD is a rare,hereditary,neurodegenerative disorder causing progressive motor impairment,cognitive decline,and psychiatric symptoms.The associated motor symptoms include jerky and unpredictable movements in the face,arms,

75、and legs.116118The pathogenesis of HD involves a complex interplay of genetic,molecular,and cellular mechanisms that ultimately lead to neurodegeneration in specific regions of the brain(Figure 8).119122 HD is caused by a mutation in the HTT gene,which encodes for a mutant huntingtin protein(mHTT).T

76、he mHTT causes disturbances to normal cellular and neuronal functions and exacerbates neurodegeneration,including altered gene expression patterns and impaired neuronal function,survival,and plasticity,123125 eventually leading to cell death.126129 Synaptic dysfunction is also an early feature of HD

77、 that contributes to cognitive and motor impairments.130,131Huntingtons diseaseHuntingtons disease pathogenesis3Motor neuronNucleusmHTT aggregates4mHTT impaired delivery to synapsesAxonal transport5Neuroinflammation leads to neurodegenerationExcess glutamate?Fragmentation?Oxidative stress?EnergyMuta

78、tionsThe main mutation in HD is a CAG repeat in HTT,which encodes for mHTT121 mHTT causes misfolding and aggregation of the protein,creating the so-called inclusion bodies and accumulating within neurons.2 Mitochondrial function is affected,impairing energy production,increasing oxidative stress,and

79、 mitochondrial fragmentation.3 Dysregulation of glutamate signaling and excitotoxicity from astrocyte dysfunction may occur.4 Axonal transport and synaptic processes are affected,with mHTT impairing the delivery of essential proteins and organelles to synapses.5 Neuroinflammation contributes to HD p

80、athogenesis.RARE DISEASES REPORT|13Figure 9.Genes associated with HD,based on data from the CAS Content Collection.Only genes with an association score greater than 0.8 and at least ten records are included.Color corresponds to association score:yellow(1.0),green(0.9)and orange(0.8).The majority of

81、records were gathered from text mining.Currently,no cure is available for HD,with treatments focusing on managing symptoms and improving quality of life.Disease-modifying treatments are the goal of ongoing research efforts,and an increased understanding of the underlying mechanisms of HD is importan

82、t to achieve this.Current clinical trials focus on therapies that target the mutant huntingtin protein,neuroinflammation,and other factors of HD pathogenesis.144,145HD is an“autosomal dominant”disease,meaning affected individuals may have only inherited one expanded CAG repeat from one of their pare

83、nts.The age of onset and severity of symptoms can vary widely among individuals,146 but often,the longer the CAG repeats,the earlier the onset and the higher the severity of the disease.119,126,147,148 Other genetic factors may also influence the onset and progression pattern of HD,and predictive ge

84、netic testing is available to help inform individuals at risk of HD.Those invited for testing are advised to attend genetic counseling to discuss their results with a genetic counselor and any potential repercussions.149,150Despite the established role of HTT in HD pathogenesis,151 this analysis als

85、o investigated other potential genetic contributors to the development of HD,with additional genes identified(Figure 9).RoleMutations to the HTT gene and resulting mHTT are well-established causes of HD.Mutations may affect synaptic plasticity and reduced levels are observed in HD.ProteinHuntingtinB

86、rain-derived neurotrophic factorGeneHTT 1.0BDNF 0.9Huntingtons diseaseGeneSIRT1 0.8HAP1 0.8PPAR GC1A 0.8CNTF 0.8IGF1 0.8ProteinSirtuin 1Huntingtin associated protein 1Peroxisome proliferator-activated receptor(PPAR)-coactivator 1 (PGC-1)Ciliary neurotrophic factorInsulin-like growth factor 1RoleSirt

87、uin 1 is a type of deacetylase that appears to have a neuroprotective effect in HD.There is evidence that HAP1 protein interacts with mHTT,which impairs cellular trafficking.mHTT has been shown to inhibit PGC-1 expression,which plays a role in mitochondrial energy metabolism.The ciliary neurotrophic

88、 factor is a cytokine with possible positive effects on demyelination,which may have a neuroprotective role in HD.The IGF1 protein acts as a mediator of growth hormone,is critical,in somatic growth,and has been associated with declining social cognition in HD.Landscape analysisPublication growth and

89、 geographical trendsPatent and journal publications in ALS have steadily increased over the last two decades,with a similar trend for MG which has had a steeper rise since 2018.Patents in HD have also been growing consistently since 2018,and journal publications also displayed an upward trend(Figure

90、 10).All three rare diseases have a greater journal-to-patent publication ratio throughout the window of analysis.Although growth is evident in all three diseases,MG exhibited the fastest growth in the years 20032006,following which ALS took the lead since 2014,with nearly 8%relative growth between

91、20032023.Number of documents2,0001,5003,0002,5001,0005000202320212019201720152013201120092007200520032004200620082010201220142016201820202022JournalsPatentsYearANumber of documents4008006002000202320212019201720152013201120092007200520032004200620082010201220142016201820202022JournalsPatentsYearCNum

92、ber of documents1,0008001,4001,2006002004000202320212019201720152013201120092007200520032004200620082010201220142016201820202022JournalsPatentsYearBFigure 10.Publications for specific rare diseases:(A)ALS,(B)HD and(C)MG.Data includes journal and patent publications sourced from the CAS Content Colle

93、ction for 20032023.RARE DISEASES REPORT|15Reports of comorbidities were assessed in publications available from the CAS Content Collection.In ALS,hypertension and dyslipidemia are the most commonly reported comorbidities.152 This is notable,as there are ongoing debates about the potential protective

94、 role of hypertension and other cardiovascular disorders towards the prognosis and survival of patients with ALS.153,154 As well as cardiovascular-related disease,autoimmune diseases are frequently reported in this patient population,although little is known about the related clinical presentation.1

95、55 Finally,despite research in this area,the association of ALS with the risk of cancer(both generally and for specific cancers)is ambiguous and inconsistent.156,157HD has frequently been associated with depression,affecting nearly 43%of all patients,the majority of whom are female.158 Individuals w

96、ith HD have also been known to have a higher prevalence of comorbidities(musculoskeletal,cardiovascular,and psychiatric)than healthy individuals.159 Conditions more commonly observed in patients with adult-onset HD versus healthy individuals include obsessive-compulsive disorder,psychosis,communicat

97、ion disorders,depression,anxiety,dementia,and others.160Both autoimmune and non-autoimmune comorbidities are observed in patients with MG,161,162 with autoimmune thyroiditis,SLE,and rheumatoid arthritis being the most frequent.163 Comorbidity onset may be related to MG disease onset,as patients with

98、 early-onset MG are more likely to develop an autoimmune disease than their late-onset counterparts.163 A known non autoimmune comorbidity of MG is cardiovascular disease.164Using the CAS Content Collection,we examined the co-occurrences of ALS,HD,and MG with other rare and non-rare diseases(Figure

99、11).ComorbiditiesARare diseasesDiseasesHD:7,897MS:15,081FTD:3,984PSP:3,501CJD:3,457SLE:5,238Spinocerebellar ataxia:2,566MG:1,200ALS:7,024Fredreich ataxia:962Sjgrens syndrome:2,457Scleroderma:2,325Autoimmune thyroiditis:2,292Graves disease:2,075GBS:1,857Ankylosing spondylitis:1,600ALSHDMGAD:23,016Par

100、kinsons disease:22,532Stroke:8,382Neoplasm:6,536Dementia:6,712Epilepsy:5,542Schizophrenia:5,727Rheumatoid arthritis:6,271Depression:2,900Autoimmune disease:3,348Psoriasis:2,295Crohns disease:2,680Type 1 diabetes:2,500Ulcerative colitis:2,411Inflammatory bowel disease:2,176Asthma:2,171CCellsProteinsT

101、DP-43:2,121-Amyloid:2,224Tau proteins:1,756Soluble tumor necrosis factors:1,750Interleukin 6:1,735FUS:654Interleukin 1:972Glial fibrillary acidic protein:894Cytokines:1,464BDNF:1,200TNF:323Type II interferons:664IgG:634Interleukin 2:542Interleukin 10:481Chimeric fusion protein:412Interleukin 4:353AL

102、SHDMGAstrocyte:2,062Microglia:1,767Neuroglia:1,184Stem cells:1,171Induced pluripotent stem cells:840T cells:1,788Macrophage:1,138Oligodendrocytes:488Fibroblasts:809Neural stem cells:797Embryonic stem cell:268B cell:673CD4-positive T cell:468Dendritic cell:341CD8-positive T cell:261NK cells:228p53:30

103、5IgG1:446Regulatory T cell:396Lymphocyte:285Mononuclear leukocyte:253BDrugsTypes of therapyALSHDMGAnti-alzheimer:12,376Anti-parkinson:11,068Neuroprotective:8,115Anti-tumor:8,328Anti-inflammatory:7,833Nervous system agents:5,390Anti-diabetic:5,695Anti-convulsants:3,790Anti-psychotics:4,198Anti-depres

104、sants:4,144Anti-rheumatic:1,888Immunosuppressants:1,564Anti-asthmatics:1,419Anti-arthritis:1,395Immunomodulators:1,255Anti-psoriatic:850Combination chemotherapy:4,448Gene therapy:1,707Chemotherapy:844Immunotherapy:1,173Radiotherapy:739Cellular therapy:457Hormone replacement therapy:127Physiotherapy:

105、78Photodynamic therapy:53Electrotherapy:51Enzyme replacement therapy:24Psychotherapy:27Phototherapy:50Figure 11.Co-occurrences of ALS,HD,and MG with medical topics such as(A)other rare and non-rare diseases,(B)types of therapy and drugs used to treat symptoms and(C)cells and proteins.Data include pa

106、tent and journal publications sourced from the CAS Content Collection for the period 20032023 in the field of rare diseases.Types of therapyCombination therapies are the most common type of treatment for all three rare diseases.This is perhaps no surprise given that ALS and HD are multifactorial dis

107、eases,meaning single-target drugs are likely to be insufficient when compared with combination drug therapy,which involves multifunctional and biologically diverse agents.165Certain topic combinations are more likely to occur than other combinations in rare disease publications.MG occurs most freque

108、ntly with combination therapy and secondly with the topic of immunotherapy,whereas ALS and HD often co-occur with gene therapy.Over 50 gene mutations have been identified with a potential causative role in ALS,and efforts are being made to understand the role of these genes in ALS pathogenesis.Due t

109、o the potential of gene therapy,suppressing the toxic impact of etiologic genes has been widely investigated.Major strategies include:removal or inhibition of abnormally transcribed ribonucleic acid(RNA)using micro RNA or antisense oligonucleotides(ASOs);degradation of abnormal messenger RNA using R

110、NA interference;a decrease in or inhibition of mutant proteins by using,for example,antibodies against misfolded proteins;and/or deoxyribose nucleic acid(DNA)genome editing with methods such as Clustered Regularly Interspaced Short Palindromic Repeats(CRISPR)or CRISPR/Cas.166 As some studies have sh

111、own positive results,ALS clinical trials have incorporated these strategies for C9orf72 and SOD1.166169HD is a good candidate for gene therapy as a monogenic disease with mHTT as a known cause.Genetic therapies may,therefore,help to enhance the function of affected genes throughout the disease cours

112、e and slow progression.170 Removing,known as“knocking out”the HTT gene has recently been tested,with promising results.171Immunotherapeutic biologics also show some promise as therapeutic agents for MG,including two monoclonal antibodies known as eculizumab and rituximab.Eculizumab has been approved

113、 by the US Food and Drug Administration for the treatment of MG that does not respond to other therapies,172 and rituximab is in the advanced stages Promising areas of therapy,drug,and target researchof clinical trials.As new biologics become available,targeted immunotherapies with higher specificit

114、y for MG may be developed.Repurposed drugsAs the pharmaceutical development process is both time-consuming and costly,drug repurposing provides a chance to accelerate therapy discovery and development.During drug repurposing,approved agents with established safety profiles,pharmacokinetics,formulati

115、ons,dosages,and manufacturing procedures are explored as treatment options for new conditions.Within the CAS Content Collection,ALS and HD most frequently co-occurred with mention of anti-Alzheimer and anti-Parkinson drugs.Ropinirole,a treatment for Parkinsons disease,has been found to delay the pro

116、gression of ALS,173 while allopurinol and carvedilol,treatments for gout and high blood pressure,respectively,show evidence of reducing the risk of developing ALS.174,175 The brain-permeable iron chelator M30 has also been associated with neuroprotection across neurodegenerative diseases.176,177 Oth

117、er drug classes have been explored for the treatment of ALS,such as anti-cancer,antiretroviral,anti-inflammatory,anticonvulsant,and antiestrogen drugs.178 Antipsychotic therapies have also been studied for use in ALS and HD.178181 Other repurposed drugs used to treat HD include tetrabenazine(an anti

118、psychotic also used for diseases involving abnormal,involuntary movements),179 tiapride,180 olanzapine,182 risperidone,181 and quetiapine.183Contrastingly,MG frequently co-occurred with immunosuppressive and anti-rheumatic drugs within the CAS Content Collection,as they may act by helping to dampen

119、the immune systems response and prevent it from attacking the NMJ.Such therapies include prednisone,azathioprine,cyclophosphamide,methotrexate,tacrolimus,mycophenolate,and mofetil.184187 Two drugs used for treating rheumatoid arthritis,abatacept and rituximab,are also reported to help prevent MG and

120、 reduce the risk of deterioration,respectively.187,188RARE DISEASES REPORT|17Small moleculesProtein/peptide sequencesNucleic acids sequencesOthersALS59%16%16%9%Relative growth(%)in substancesassociated with journal publicationsPublication year40353025201510502012 2013 2014 2015 2016 2017 2018 2019 2

121、020 2021 2022 2023Small moleculesProtein/peptide sequencesNucleic acids sequencesOthersRelative growth(%)in substancesassociated with patent publicationsPublication year3025201510502012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023Small moleculesProtein/peptide sequencesNucleic acids sequen

122、cesOthersAmyotrophic lateral sclerosis(ALS)AProteinsPatterns of co-occurrences of rare diseases with proteins were also analyzed;for example,transactive response DNA binding protein 43(TDP-43)had the highest co-occurrence with ALS.In 97%of cases,ALS is characterized by loss of TDP-43 from the nucleu

123、s and abnormal accumulation in the cytoplasm of affected neurons,189191 and has been related to disease severity and progression.192While huntingtin is the key protein in HD etiology,recent research has revealed the presence of-amyloid deposits and elevated levels of phosphorylated tau in the brains

124、 of patients despite these being typically associated with Alzheimers disease.193195 CellsThe CAS Content collection determined astrocytes and microglial cells as the most frequently co-occurring cells associated with ALS and HD publications,whereas T-and B-cells are commonly associated with MG.Astr

125、ocytes have roles in ALS and HD throughout the disease course through various mechanisms.196 Microglia are immune cells initially recruited to respond to neuronal injury and promote tissue repair but may become chronically activated in ALS and HD,leading to further motor neuron degeneration.196198 O

126、ther cell types including oligodendrocytes and NG2 glia,may also play a part in ALS and HD pathology.16,199,200Substance dataThe CAS Registry contains over 250 million substances of diverse classes.Between 20122023,the number of patent publications related to small molecules,protein/peptide sequence

127、s,and nucleic acid sequences increased(Figure 12),with no similar trend observed in journal publications.This is indicative of a commercial interest in developing these therapeutics.For ALS,HD,and MG,small molecules represented the largest fraction of explored substances(Figure 12).RARE DISEASES REP

128、ORT|19Small moleculesProtein/peptide sequencesNucleic acids sequencesOthersHD70%12%11%7%Relative growth(%)in substancesassociated with journal publicationsPublication year10090807060504030201002012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023Small moleculesProtein/peptide sequencesNucleic

129、acids sequencesOthersRelative growth(%)in substancesassociated with patent publicationsPublication year353025201510502012013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023Small moleculesProtein/peptide sequencesNucleic acids sequencesOthersHuntingtons disease(HD)BSmall moleculesProtein/peptide se

130、quencesNucleic acids sequencesOthersMG13%67%13%6%Relative growth(%)in substancesassociated with journal publicationsPublication year35302520151050201 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023Small moleculesOthersRelative growth(%)in substancesassociated with patent publicationsPublicati

131、on year353025201510502012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023Small moleculesProtein/peptide sequencesNucleic acids sequencesOthersMyasthenia gravis(MG)CFigure 12.Substance data from the CAS Registry is associated with(A)ALS,(B)HD and(C)MG.Data includes substances associated with p

132、atent and journal publications sourced from the CAS Registry and the CAS Content Collection for the period 20122023.Figure 13.Commercial interest in rare diseases(data sourced from PitchBook,an online platform for investment data).Capital invested and deals related to rare diseases(HD,ALS,MG)for the

133、 past decade(20122023).Rare diseases such as ALS,HD,and MG have been the subject of intense research and investment over the past decade,as confirmed by data from Pitchbook,an online platform for investment data.However,a mild decline has been observed in the amount of money invested in this field o

134、ver the last three years(20212023),which could indicate a slight decrease in commercial interest(Figure 13).Between 20132023,the greatest amount of financial investment came from the US,followed by Belgium,the Netherlands,and the UK.The top industry investors in rare diseases are life sciences based

135、,followed by oncology and healthtech.Vaccinex,a US-based biotech company,has the highest number of deals in this field.Its lead drug candidate,pepinemab,has been identified as a potential disease-modifying treatment for HD,Alzheimers,and other neurodegenerative diseases and is currently being invest

136、igated in Phase II clinical trials.201,202 Another biotech company,Cytokinetics,is investing in diseases linked to the NMJ,such as ALS.203 These trends confirm a solid commercial interest in rare diseases,including ALS,HD,and MG.What story does the financial data tell?Capital investment(Log scale)De

137、al count$1.00B$100.00M$100.00B$10.00B$10.00M$1.00M60508070403020100202320222021202020192018201720162015201420132012Capital investmentDeal countPublication yearRARE DISEASES REPORT|21What is in the pipeline?Nearly 250 substances are being researched and in preclinical development for treating ALS,HD,

138、and MG(Tables 1,2,and 3).The vast majority(74%)of these substances are for the treatment of ALS,but therapies for the treatment of HD(18%)and MG(8%)are also in the development pipeline.Small molecule drugs dominate the total number of drug candidates,followed by gene,antibody,RNA,ASO,and stem cell t

139、herapies(Figure 14).Rare disease therapeutic drug candidates in commercial preclinical development (Source:https:/ candidatesAmyotrophic lateral sclerosis(ALS)ForalumabMonoclonal antibody,humanizedCD3 antagonistTiziana Life Sciences,UKMecobalaminNeuroprotectantVitamin B12 agonistEisai,JapanMitometin

140、Cognition enhancer,neuroprotectantCarnitine palmitoyltransferase 1 inhibitor2N Pharma,DenmarkPimicotinibNeuroprotectantColony stimulating factor 1 receptor antagonist;immuno-oncology therapySperogenix Therapeutics,ChinaRifampicinCognition enhancer,neuroprotectantDNA-directed RNA polymerase inhibitor

141、Medilabo RFP,JapanRiluzoleNeuroprotectantDopamine receptor agonist;glutamate antagonist;voltage-gated sodium channel antagonistBrain Trust Bio,USATable 1.Examples of therapeutic drug candidates in ALS.Huntingtons disease(HD)Debamestrocel Stem cell therapyGlial-cell-derived neurotrophic growth factor

142、 agonistBrainStorm Cell Therapeutics,USAHD therapy PROTACHTT inhibitor;E3 ubiquitin ligase stimulant,protein degraderArvinas,USAHD therapy Cognition enhancer,neuroprotectantReverses mitochondrial dysfunctionMitoRx Therapeutics,UKHD therapy RNA interferenceUtilizing a small hairpin RNA or short hairp

143、in RNA for gene expression inhibitionNovartis,Switzerland;Voyager Therapeutics,USATable 2.Examples of therapeutic drug candidates in HD.Myasthenia gravis(MG)Equecabtagene autoleucelCAR T-cell therapyImmuno-oncology therapy;T-cell stimulantNanjing IASO Biotechnology,ChinaPozelimabMonoclonal antibody,

144、humanizedC5a inhibitorRegeneron,USAPrednisoneMusculoskeletal therapyGlucocorticoid agonistSarcomed ABTable 3.Examples of therapeutic drug candidates in MG.RARE DISEASES REPORT|23Small moleculeExosome therapyHuntingtons diseaseAmyotrophic lateral sclerosisMyasthenia gravisGene therapyAntisense oligon

145、ucleotide therapyStem cell therapyRNA interferenceAntibody therapyFusion protein therapyProtein degraderPeptide therapyRNA therapyCAR T-cell therapyFigure 14.Preclinical drug therapy candidates and their respective rare disease indications that are currently in the development pipeline.Figure 15.Num

146、ber of clinical trials by rare disease indications for the years 20032023.As part of the exploration of these new rare disease therapies,over 1 thousand clinical trials have been registered on the US National Institutes of Health clinical trial website over the last 20 years.ALS has the highest numb

147、er of registered trials,followed by HD and MG(Figure 15).Number of clinical trials806012010040200202320222021202020192018201720162015201420132012201120102009200820072006200520042003Myasthenia gravisHuntingtons diseaseAmyotrophic lateral sclerosisYearNearly half of all rare disease clinical trials ar

148、e not phased;for those that are,Phase II and Phase III studies are the most common phase of trial for ALS/HD and MG,respectively.While almost half of all trials for these three diseases have a status of“completed”,”recruiting”is the second-most common status,suggesting a continued interest in this s

149、pace.In ALS,therapy types in clinical development include cell and gene therapies,and small-molecule drugs.RAPA Therapeutics is developing a candidate for autologous T-cell therapy,RAPA-501,to address the limited options for the treatment of neuroinflammation.They are currently recruiting for a Phas

150、e II/II clinical trial(NCT04220190)to assess its safety and efficacy in standard-risk patients.204 Additionally,a gene therapy agent,AMT-162 from UniQure Biopharma,will soon be evaluated in patients with SOD1 mutations and rapidly progressive disease(NCT06100276).Rare disease research is also no exc

151、eption to the application of artificial intelligence(AI),which helped to discover the small molecule FB1006 for the potential treatment of ALS.205 Two more small molecules,ibudilast(CAS RN:50847-11-5)and pridopidine(CAS RN:346688-38-8),discovered by MediciNova and Prilenia respectively,are being inv

152、estigated as part of the HEALEY ALS Platform trial(NCT04297683).The latter was granted orphan drug designation in 2021 from the US Food and Drug Administration(FDA).206In HD,therapies under development include ASO,cell,and monoclonal antibody therapies,computer-based cognitive stimulation,and small-

153、molecule agents.One such ASO is WVE-003 from Wave Life Sciences,a gene-silencing therapeutic.Further biological-based therapies include NestaCell,a stem cell therapy discovered by Cellavita,which is currently being evaluated in Phase I and Phase II/III clinical trials(NCT02728115 and NCT04219241).A

154、pioneering study by Santa Cre Hospital(Spain)is investigating computer-based cognitive rehabilitation(NCT05769972)in patients with movement disorders.Sage Therapeutics is currently recruiting for Phase II/III clinical trials(NCT05107128,NCT05358821,and NCT05655520)for their small molecule drug SAGE

155、718(CAS RN:1629853-48-0).SAGE 718 was granted FDA Fast Track designation207 in 2022 and Orphan Drug Designation in 2023,an indication of its promise towards HD.208Therapies under development for MG include biologics such as antigen,cell,and fusion proteins,as well as small molecule-based treatments.

156、COUR Pharmaceutical is developing CNP-106,an antigen-specific therapeutic that prevents immune-mediated NMJ destruction and aims to reprogram the immune system to address the immunological root cause of MG(NCT06106672).An mRNA CAR-T cell therapy currently under investigation is Descartes 08,by Carte

157、sian Therapeutics.Preliminary results for Descartes 08 indicate it is well tolerated,with meaningful improvement in MG disease scorings(NCT04146051),209 and the FDA has granted it Orphan Drug Designation in 2024.210 Another biological therapy is telitacicept,a fusion protein constructed of a domain

158、of an extracellular protein from B cells and immunoglobulin G,from RemeGene.211 RemeGene is currently recruiting for a Phase III clinical trial(NCT05737160).212(Figure 16).Finally,Alexion Pharmaceuticals is currently investigating their candidate ALXN2050(CAS RN:2086178-00-7),a small molecule factor

159、 D inhibitor,in a Phase II clinical trial(NCT05218096).Targets B-cell development key molecules:B-cell lymphocyte stimulator and a proliferation-inducing ligandB-cell mediated autoimmune responsesMG-related symptomsTolerable safety profileAnti-AChR antibodiesAChAChRNeuronMuscleFigure 16.Mode of acti

160、on of telitacicept,a fusion protein-based therapy.Telitacicept interacts with B cells to decrease the resulting mediated immune response and anti-AChR antibodies,and thus,decreases MG symptoms.TelitaciceptRARE DISEASES REPORT|25FDA approved small molecule and biological drugs for rare diseasesStruct

161、ure/therapy typeCAS Registry NumberMechanism and notesCompany,locationExservan (riluzole)for ALS FFFONNHHS1744-22-5Glutamate signaling blocker/oral film formulationMitsubishi Tanabe Pharma America,USANuedexta(dextromethorphan hydrobromide and quinidien sulfate)for ALSNHHO 2445595-41-3Sigma-1 recepto

162、r agonist,NMDA receptor antagonistOtsukac America Pharmaceutical,USAONOHOOOOHSHNHHRadicava (edaravone)for ALSONN89-25-8Free radical scavengerMitsubishi Tanabe Pharma America,USARelyvrio(sodium phenylbutyrate and taurursodiol)for ALSOONa+2436469-04-2Small molecule chaperone and Bax inhibitor/withdraw

163、n 2024Amylyx,USAHHHHHHHHOOOOOSOHHRilutek(riluzole)for ALSFOFFSNNHH1744-22-5Glutamate signaling blocker/oral tablet formulationSanofi,USACurrently,there are no cures for ALS,HD,or MG,but there are treatments to slow disease progression and treat symptoms.There are 13 drugs currently approved by the F

164、DA for treating these rare diseases,of which three have multiple approved formulations(Table 4).Several of the approved drugs for ALS and HD are small molecules.In contrast,biologic therapies such as monoclonal antibodies,antibody fragments,and peptide therapy make up most of the approved treatments

165、 for MG.Patents pertaining to ALS,HD,and MG were identified from the CAS Content Collection(Table 5).What could the future hold?FDA approved small molecule and biological drugs for rare diseasesStructure/therapy typeCAS Registry NumberMechanism and notesCompany,locationTiglutik(riluzole)for ALSFOFFS

166、NNHH1744-22-5Glutamate signaling blocker/oral thickened suspensionITF Pharma,USAAustedo(deutetrabenazine)for HDNOOHDDDDDDOO1392826-25-3 VMAT2 inhibitorTeva Pharmaceutical,IsraelAustedo XR(deutetrabenazine)for HDOOHDDDDDDOO1392826-25-3VMAT2 inhibitor/extended-release formulationTeva Pharmaceutical,Is

167、raelIngrezza(valbenazine)for HDOOHHHNNOO1025504-45-3VMAT2 inhibitorNeurocrine Biosciences,USAXenazine(tetrabenazine)for HDOONO58-46-8VMAT2 inhibitorLundbeck Pharmaceuticals,DenmarkRARE DISEASES REPORT|27FDA approved small molecule and biological drugs for rare diseasesStructure/therapy typeCAS Regis

168、try NumberMechanism and notesCompany,locationQalsody(tofersen)for ALSGene therapy2088232-70-4Targets SOD1 mRNA to reduce SOD1 protein productionBiogen,USARystiggo(rozanolixizumab-noli)for MGMonoclonal antibody 1584645-37-3 Targets FcRn to prevent IgG recyclingUCB,USASoliris (eculizumab)for MGMonoclo

169、nal antibody 219685-50-4Complement factor C5 inhibitorAlexion,UKUltomiris(ravulizumab-cwvz)for MGMonoclonal antibody 1803171-55-2Complement factor C5 inhibitorAlexion,UKVyvgart(efgartigimod alfa-fcab)for MGAntibody fragment1821402-21-4Fc receptor blocker,intravenous injection Argenx,NetherlandsVyvga

170、rt Hytrulo(efgartigimod alfa and hyaluronidase-qvfc)for MGAntibody fragment 1821402-21-4Fc receptor blocker,subcutaneous injectionArgenx,NetherlandsZilbrysq (zilucoplan)for MGPeptide therapy1841136-73-9Complement factor C5 inhibitorUCB,USATable 4.FDA-approved drugs for the treatment of specified rar

171、e diseases(Source:The CAS Content Collection).Each drug is listed with the disease indication,therapy type,CAS identifier,mechanism,company,location,and any extra information.Tile colors are defined by therapy type:small molecule(yellow),gene therapy(orange),monoclonal antibody(blue),antibody fragme

172、nt(light green),and peptide therapy(purple).Patent numberYearPatent assignee,locationDescriptionALSUS202000027232020Deutsches Krebsforschungszentrum,GermanyEarly markers for development:nucleotide sequences called Multiple Sclerosis Brain Isolate(MSBI),as well as probes,primers,and antibodies agains

173、t polypeptides encoded by MSBI sequencesWO20200100492020The General Hospital Corporation,AZTherapies,Inc.,United StatesTreatment:composition of micronized cromolyn sodium,-lactose,and salt of fatty acid(preferably magnesium stearate)CN1170501342023Shanghai Institute of Organic Chemistry,Chinese Acad

174、emy of Sciences,ChinaTreatment and prevention:novel oleanamide derivative for activating a KEAP/NRF2/ARE signaling pathwayEP4255406A12020Massey Ventures Ltd.,United StatesTreatment:(2S)-2-Aminopentanethioic S-acid or a pharmaceutically acceptable saltWO20221387072022Eisai R&D Management Co.,Ltd.,Jap

175、anTreatment:pharmaceutical composition of anti-EphA4 antibodies that promote the cleavage of EphA4HDWO20230996482023AstraZeneca AB,SwedenTreatment:pyrazolo-and triazolo-azinone compounds that inhibit receptor-interacting protein kinase 1US20240076310A12023Sage Therapeutics Inc.,United StatesTreatmen

176、t:neuroactive steroids(or their combinations),that target GABA receptor complex(GRC)WO2022235329A12022University of South Carolina,United StatesTreatment:hydrophilic nanogels based on polyethylene glycol(PEG)copolymers to encapsulate an antibody for delivery to the brain.May include ligands for bloo

177、d-brain barrier receptorsWO2022132894A12022Rush University Medical Center,United StatesTreatment:pharmaceutical composition of glycerol tribenzoate and glycerol phenylbutyrateWO2020068913A12020Chase Therapeutics Corporation,United StatesTreatment:combination 5HT3-antagonist and/or a NK-l antagonist

178、with 6-propylamino-4,5,6,7-tetrahydro-l,3-benzothiazole-2-amine and with fluoxetine,zonisamide,or a statinMGWO2020106724A12020Alexion Pharmaceuticals,Inc.,United StatesTreatment(pediatric population):formulation that binds complement component 5WO2020014072A12020GT Biopharma,Inc.,United StatesTreatm

179、ent:NK1-antagonist(e.g.,aprepitant)in combination with neostigmine.WO2023236967A12023RemeGene Co.,Ltd.,ChinaTreatment:development of the drug,a dosage regimen,an administration interval,and a mode for treating MG using TACI-Fc fusion protein,showing good clinical efficacy and safetyWO2020086506A1202

180、0Ra Pharmaceuticals,Inc.,United StatesTreatment:methods of treating MG with zilucoplan(complement inhibitor),including devices and kits available for administrationCN112048565A2020Shijiazhuang Peoples Hospital,ChinaDiagnosis:microbial marker(comprising Megamonas hypermegale and/or Fusobacterium mort

181、iferum)with good specificity and high sensitivityTable 5.List of notable patents pertaining to ALS,HD,and MG identified from the CAS Content Collection.SummaryCurrent landscape,challenges,and possible future perspectivesIn the vast landscape of medical conditions,rare diseases occupy a unique and of

182、ten overlooked niche.Despite their low prevalence,these disorders collectively affect millions worldwide.2,3 Each rare disease represents a unique manifestation of genetic,environmental,and/or infectious factors,often with distinct clinical presentations.This variation means initial diagnosis and on

183、going treatment may be challenging.Research into rare diseases has uncovered many novel disease mechanisms,with advances in genomics,molecular biology,and precision medicine holding promise for improved diagnosis and targeted therapies.Insights gained from studying underlying mechanisms of rare dise

184、ases have broad implications for understanding more prevalent disorders,such as progerin in HGPS and possible links to cardiovascular disease.Future research into rare diseases will hopefully continue to identify druggable targets and novel therapeutic strategies.Despite these advances,significant r

185、oadblocks remain to progress in rare disease research and care.The small size of patient populations limits the potential for robust clinical trials,leading to fewer evidence-based treatment options.Even once research is underway,the confidentiality associated with scientific research(including rare

186、 diseases)can impede collaboration and knowledge sharing among the scientific community.Historically,there has been a lack of commercial incentives for developing treatments for rare diseases,accounting for a lack of interest from the pharmaceutical industry.However,new incentives are beginning to c

187、hange this.Collaborative and regulatory incentives and patient-centered trial designs are accelerating the translation of scientific discoveries into clinically meaningful interventions.Furthermore,sharing data and resources through collaborative platforms and consortia has become a cornerstone of r

188、are disease research.Continued investment in rare disease research,infrastructure,and policy initiatives is critical for overcoming existing challenges and maximizing the potential of scientific advancements to improve the lives of people living with rare diseases.RARE DISEASES REPORT|291.Abozaid,G.

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