克雅病治疗策略的研究进展

doi:10.13481/j.1671-587X.20260429

Abstract

Abstract:

Creutzfeldt-Jakob disease （CJD） is a fatal neurodegenerative disorder caused by prions， characterized by a rapidly progressing clinical course. Diagnosis often occurs in the mid-to-late stages， and the fast disease progression and high lethality pose significant challenges for clinical treatment. Although understanding of prions has deepened in terms of molecular mechanisms， effective interventions and drugs remain lacking in clinical diagnosis and management. Based on the latest domestic and international research advances in the treatment of CJD， this article summarized and reviewd the main research directions and recent achievements in CJD treatment. It coverd four aspects： historical drug therapies， immunotherapy， gene therapy， and emerging treatment strategies. The mechanisms， preclinical studies， and clinical trial outcomes of various approaches were summarized and evaluated. The breakthroughs and limitations of current treatment strategies were discussed to provide the foundation for exploring future research directions and developing novel therapies.

Key words: Creutzfeldt-Jakob disease, Prion, Treatment strategy, Neurodegenerative disease, Drug development

CLC Number:

R741

Dongyue JIANG,Li CUI. Research progress in therapeutic strategies for Creutzfeldt-Jakob disease[J].Journal of Jilin University(Medicine Edition), 2026, 52(4): 1161-1169.

References 58

[1]	UTTLEY L， CARROLL C， WONG R， et al. Creutzfeldt-Jakob disease： a systematic review of global incidence， prevalence， infectivity， and incubation［J］. Lancet Infect Dis， 2020， 20（1）： e2-e10.
[2]	ZERR I， LADOGANA A， MEAD S， et al. Creutzfeldt-Jakob disease and other prion diseases［J］. Nat Rev Dis Primers， 2024， 10（1）： 14.
[3]	SIGURDSON C J， BARTZ J C， GLATZEL M. Cellular and molecular mechanisms of prion disease［J］. Annu Rev Pathol， 2019， 14： 497-516.
[4]	BÜELER H， AGUZZI A， SAILER A， et al. Mice devoid of PrP are resistant to scrapie［J］. Cell， 1993， 73（7）： 1339-1347.
[5]	GESCHWIND M D， KUO A L， WONG K S， et al. Quinacrine treatment trial for sporadic Creutzfeldt-Jakob disease［J］. Neurology， 2013， 81（23）： 2015-2023.
[6]	OTTO M， CEPEK L， RATZKA P， et al. Efficacy of flupirtine on cognitive function in patients with CJD： a double-blind study［J］. Neurology， 2004， 62（5）： 714-718.
[7]	DE LUIGI A， COLOMBO L， DIOMEDE L， et al. The efficacy of tetracyclines in peripheral and intracerebral prion infection［J］. PLoS One， 2008， 3（3）： e1888.
[8]	HAÏK S， MARCON G， MALLET A， et al. Doxycycline in Creutzfeldt-Jakob disease： a phase 2， randomised， double-blind， placebo-controlled trial［J］. Lancet Neurol， 2014， 13（2）： 150-158.
[9]	GROVEMAN B R， FERREIRA N C， FOLIAKI S T， et al. Human cerebral organoids as a therapeutic drug screening model for Creutzfeldt-Jakob disease［J］. Sci Rep， 2021， 11（1）： 5165.
[10]	SHIJO M， YOSHIMURA M， OMAE T， et al. Altered properties of amyloidogenic prion protein in genetic Creutzfeldt-Jakob disease with PRNP V180I mutation in response to pentosan polysulfate［J］. Brain Pathol， 2023， 33（5）： e13197.
[11]	HEPPNER F L， MUSAHL C， ARRIGHI I， et al. Prevention of scrapie pathogenesis by transgenic expression of anti-prion protein antibodies［J］. Science， 2001， 294（5540）： 178-182.
[12]	WHITE A R， ENEVER P， TAYEBI M， et al. Monoclonal antibodies inhibit prion replication and delay the development of prion disease［J］. Nature， 2003， 422（6927）： 80-83.
[13]	REIMANN R R， SONATI T， HORNEMANN S， et al. Differential toxicity of antibodies to the prion protein［J］. PLoS Pathog， 2016， 12（1）： e1005401.
[14]	MEAD S， KHALILI-SHIRAZI A， POTTER C， et al. Prion protein monoclonal antibody （PRN100） therapy for Creutzfeldt-Jakob disease： evaluation of a first-in-human treatment programme［J］. Lancet Neurol， 2022， 21（4）： 342-354.
[15]	NAPPER S， SCHATZL H M. Vaccines for prion diseases： a realistic goal？［J］. Cell Tissue Res， 2023， 392（1）： 367-392.
[16]	ABDELAZIZ D H， THAPA S， ABDULRAHMAN B， et al. Immunization of cervidized transgenic mice with multimeric deer prion protein induces self-antibodies that antagonize chronic wasting disease infectivity in vitro ［J］. Sci Rep， 2017， 7（1）： 10538.
[17]	FLEMING M. Optimization and analysis of structure- based prion vaccines in transgenic mouse models［D］. Edmonton： University of Alberta， 2013.
[18]	PFEIFER A， EIGENBROD S， AL-KHADRA S， et al. Lentivector-mediated RNAi efficiently suppresses prion protein and prolongs survival of scrapie-infected mice［J］. J Clin Invest， 2006， 116（12）： 3204-3210.
[19]	PEASE D， SCHECKEL C， SCHAPER E， et al. Genome-wide identification of microRNAs regulating the human prion protein［J］. Brain Pathol， 2019， 29（2）： 232-244.
[20]	KANG S G， KIM C， AIKEN J， et al. Dual microRNA to cellular prion protein inhibits propagation of pathogenic prion protein in cultured cells［J］. Mol Neurobiol， 2018， 55（3）： 2384-2396.
[21]	GHEIBI-HAYAT S M， JAMIALAHMADI K. Antisense oligonucleotide （AS-ODN） technology： principle， mechanism and challenges［J］. Biotechnol Appl Biochem， 2021， 68（5）： 1086-1094.
[22]	NAZOR FRIBERG K， HUNG G， WANCEWICZ E， et al. Intracerebral infusion of antisense oligonucleotides into prion-infected mice［J］. Mol Ther Nucleic Acids， 2012， 1（2）： e9.
[23]	PREUßNER M， SMITH H L， HUGHES D， et al. ASO targeting RBM3 temperature-controlled poison exon splicing prevents neurodegeneration in vivo ［J］. EMBO Mol Med， 2023， 15（5）： e17157.
[24]	MORTBERG M A， GENTILE J E， NADAF N M， et al. A single-cell map of antisense oligonucleotide activity in the brain［J］. Nucleic Acids Res， 2023， 51（14）： 7109-7124.
[25]	WEBSTER P， HEALEY N. Eleven clinical trials that will shape medicine in 2025［J］. Nat Med， 2024， 30（12）： 3384-3388.
[26]	CHOU S W， MORTBERG M A， MARLEN K， et al. Zinc Finger Repressors mediate widespread PRNP lowering in the nonhuman primate brain and profoundly extend survival in prion disease mice［EB/OL］. （2025-03-10）［2025-09-13］. .
[27]	CASTLE A R， WOHLGEMUTH S， ARCE L， et al. Investigating CRISPR/Cas9 gene drive for production of disease-preventing prion gene alleles［J］. PLoS One， 2022， 17（6）： e0269342.
[28]	ASANTE E A， SMIDAK M， GRIMSHAW A， et al. A naturally occurring variant of the human prion protein completely prevents prion disease［J］. Nature， 2015， 522（7557）： 478-481.
[29]	HUANG J J， LI X N， LIU W L， et al. Neutralizing mutations significantly inhibit amyloid formation by human prion protein and decrease its cytotoxicity［J］. J Mol Biol， 2020， 432（4）： 828-844.
[30]	MEDD M M， CAO Q. Perspectives on CRISPR genome editing to prevent prion diseases in high-risk individuals［J］. Biomedicines， 2024， 12（8）： 1725.
[31]	AN M R， DAVIS J R， LEVY J M， et al. In vivo base editing extends lifespan of a humanized mouse model of prion disease［J］. Nat Med， 2025， 31（4）： 1319-1328.
[32]	NEUMANN E N， BERTOZZI T M， WU E， et al. Brainwide silencing of prion protein by AAV-mediated delivery of an engineered compact epigenetic editor［J］. Science， 2024， 384（6703）： ado7082.
[33]	BRADFORD B M， TETLOW L， MABBOTT N A. Prion disease pathogenesis in the absence of the commensal microbiota［J］. J Gen Virol， 2017， 98（7）： 1943-1952.
[34]	YANG D M， ZHAO D M， ZALI SHAH S， et al. Implications of gut microbiota dysbiosis and metabolic changes in prion disease［J］. Neurobiol Dis， 2020， 135： 104704.
[35]	TRICHKA J， ZOU W Q. Modulation of neuroinflammation by the gut microbiota in prion and prion-like diseases［J］. Pathogens， 2021， 10（7）： 887.
[36]	WANG Y， CUI J， SUN X， et al. Tunneling-nanotube development in astrocytes depends on p53 activation［J］. Cell Death Differ， 2011， 18（4）： 732-742.
[37]	ZHONG Z， GRASSO L， SIBILLA C， et al. Prion-like protein aggregates exploit the RHO GTPase to cofilin-1 signaling pathway to enter cells［J］. EMBO J， 2018， 37（6）： e97822.
[38]	NAMME J N， BEPARI A K， TAKEBAYASHI H. Cofilin signaling in the CNS physiology and neurodegeneration［J］. Int J Mol Sci， 2021， 22（19）： 10727.
[39]	ZAJKOWSKI T， NIEZNANSKA H， NIEZNANSKI K. Stabilization of microtubular cytoskeleton protects neurons from toxicity of N-terminal fragment of cytosolic prion protein［J］. Biochim Biophys Acta， 2015， 1853（10 Pt A）： 2228-2239.
[40]	ZHANG B， CARROLL J， TROJANOWSKI J Q， et al. The microtubule-stabilizing agent， epothilone D， reduces axonal dysfunction， neurotoxicity， cognitive deficits， and Alzheimer-like pathology in an interventional study with aged tau transgenic mice［J］. J Neurosci， 2012， 32（11）： 3601-3611.
[41]	SHUAIB S， NARANG S S， GOYAL D， et al. Computational design and evaluation of β-sheet breaker peptides for destabilizing Alzheimer’s amyloid-β（42） protofibrils［J］. J Cell Biochem， 2019， 120（10）： 17935-17950.
[42]	SOTO C， KASCSAK R J， SABORÍO G P， et al. Reversion of prion protein conformational changes by synthetic beta-sheet breaker peptides［J］. Lancet， 2000， 355（9199）： 192-197.
[43]	UDAYAKUMAR S， GIRIGOSWAMI A， GIRIGOSWAMI K. A review on current theories and potential therapies for prion diseases［J］. Mol Biol Rep， 2025， 52（1）： 674.
[44]	THACKRAY A M， LAM B， MCNULTY E E， et al. Clearance of variant Creutzfeldt-Jakob disease prions in vivo by the Hsp70 disaggregase system［J］. Brain， 2022， 145（9）： 3236-3249.
[45]	CHOPRA G， SHABIR S， YOUSUF S， et al. Proteinopathies： deciphering physiology and mechanisms to develop effective therapies for neurodegenerative diseases［J］. Mol Neurobiol， 2022， 59（12）： 7513-7540.
[46]	CATTEPOEL S， HANENBERG M， KULIC L， et al. Chronic intranasal treatment with an anti-Aβ（30-42） scFv antibody ameliorates amyloid pathology in a transgenic mouse model of Alzheimer’s disease［J］. PLoS One， 2011， 6（4）： e18296.
[47]	ALI T， HANNAOUI S， NEMANI S， et al. Oral administration of repurposed drug targeting Cyp46A1 increases survival times of prion infected mice［J］. Acta Neuropathol Commun， 2021， 9（1）： 58.
[48]	ALI T， CASHION J， HANNAOUI S， et al. Treatment with efavirenz extends survival in a Creutzfeldt-Jakob disease model by regulating brain cholesterol metabolism［J］. JCI Insight， 2025， 10（14）： e190296.
[49]	GARCÍA-MENDÍVIL L， MEDIANO D R， HERNAIZ A， et al. Effect of scrapie prion infection in ovine bone marrow-derived mesenchymal stem cells and ovine mesenchymal stem cell-derived neurons［J］. Animals， 2021， 11（4）： 1137.
[50]	HAY A J D， LATHAM A S， MUMFORD G， et al. Intranasally delivered mesenchymal stromal cells decrease glial inflammation early in prion disease［J］. Front Neurosci， 2023， 17： 1158408.
[51]	RELAÑO-GINÉS A， LEHMANN S， BENCSIK A， et al. Stem cell therapy extends incubation and survival time in prion-infected mice in a time window-dependant manner［J］. J Infect Dis， 2011， 204（7）： 1038-1045.
[52]	FRID K， BINYAMIN O， FAINSTEIN N， et al. Autologous neural progenitor cell transplantation into newborn mice modeling for E200K genetic prion disease delays disease progression［J］. Neurobiol Aging， 2018， 65： 192-200.
[53]	KIM H J， CHO K R， JANG H， et al. Intracerebroventricular injection of human umbilical cord blood mesenchymal stem cells in patients with Alzheimer’s disease dementia： a phase Ⅰ clinical trial［J］. Alzheimers Res Ther， 2021， 13（1）： 154.
[54]	ZAYED M， KIM Y C， JEONG B H. Therapeutic effects of adipose-derived mesenchymal stem cells combined with glymphatic system activation in prion disease［J］. Mol Neurodegener， 2025， 20（1）： 42.
[55]	SPAGNOLLI G， MASSIGNAN T， ASTOLFI A， et al. Pharmacological inactivation of the prion protein by targeting a folding intermediate［J］. Commun Biol， 2021， 4（1）： 62.
[56]	INNOCENTI N， TÄHTINEN P， SPAGNOLLI G， et al. Enantiomers of the prion protein degrader SM875： Production and configurational assignment， in silico analysis and in vitro evaluation［J］. Bioorg Chem， 2025， 161： 108489.
[57]	KIM J， LEE H， KIM H M， et al. Isolation of anti-prion compounds from curcuma phaeocaulis valeton extract［J］. Molecules， 2024， 29（17）： 4034.
[58]	DE AMORIM M S， AMARAL-DO-NASCIMENTO M， SEVERINO V G P， et al. Identification of chlorogenic acids from moringa oleifera leaves as modulators of prion aggregation using affinity selection-mass spectrometry［J］. ACS Omega， 2025， 10（3）： 2919-2930.

Research progress in therapeutic strategies for Creutzfeldt-Jakob disease

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