MicroRNA-mediated methods for rejuvenating CNS glial populations
Inventors
Goldman, Steven A. • Mariani, John N.
Assignees
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Publication Number
US-12565648-B2
Publication Date
2026-03-03
Expiration Date
Abstract
Methods of inducing rejuvenation in a population of adult glial progenitor cells, and methods of treating a subject having a myelin deficiency are disclosed in this patent application. The method of inducing rejuvenation in a population of adult glial progenitor cells, may comprise: administering, to the population of adult glial progenitor cells, one or more nucleic acid molecules encoding microRNAs, wherein administering suppresses the signal transducer and activator of transcription 3 (STAT3) signaling pathway; and/or administering microRNAs, wherein administering suppresses the E2F transcription factor 6 (E2F6) signaling pathway; and/or administering microRNAs, wherein administering suppresses the Myc-associated factor X (MAX) signaling pathway, wherein the one or more nucleic acid molecules are administered in an amount sufficient to induce rejuvenation in the population of adult glial progenitor cells.
Core Innovation
The invention relates to an isolated population of glial progenitor cells in which each cell is genetically engineered to express at least one nucleic acid molecule comprising one or more microRNAs selected from miR-125b-5p, miR-106a-5p, miR-17-5p, miR-130a-3p, miR-130b-3p, miR-379-5p, and miR-485-5p. The microRNA-based genetic engineering is directed to rejuvenation of adult CNS glial progenitor cells, including oligodendrocyte progenitor cells and NG2 cells.
In connection with this microRNA expression, the functional outcome described includes suppressing signaling pathways STAT3, E2F6, and MAX, and the document describes senescence and proliferation effects associated with the inferred transcription factor and microRNA networks. The disclosure also describes a regulatory framework that includes repressors comprising E2F6, ZNF274, MAX, and IKZF3, and an activator comprising STAT3, together with age-dependent transcription factor networks and miRNA changes associated with progenitor, proliferation, maturation, and senescence states.
The described systems include expression vectors and promoter options, including glial cell-selective promoters and inducible promoter systems such as tetracycline, cumate, and rapamycin, together with viral and non-viral expression vector formats. The described overall biology culminates in treatment of myelin deficiency in the CNS, and the document further refers to an in vivo chimeric mouse model with CBh-driven BCL11A lentivirus reporting increased proliferation and expansion of BCL11A-expressing GPC lineage and increased myelinating morphology without tumors.
Claims Coverage
The consolidated content covers an isolated population of glial progenitor cells genetically engineered to express specified microRNAs, with dependent refinements concerning promoter features and expression vector format. The inventive features repeatedly center on the microRNA set, optional additional microRNAs, and genetic control or delivery format.
Genetically engineered glial progenitor cells expressing selected microRNAs
An isolated population of glial progenitor cells, wherein each cell is genetically engineered to express at least one nucleic acid molecule comprising one or more microRNAs selected from miR-125b-5p, miR-106a-5p, miR-17-5p, miR-130a-3p, miR-130b-3p, miR-379-5p, and miR-485-5p.
Operable linkage to a glial cell-specific promoter
The isolated population of glial progenitor cells uses a glial cell-specific promoter.
Operable linkage to an inducible promoter
The gene promoter is an inducible promoter.
Expression vector delivery format
The polynucleotide or one or more nucleic acid molecules is in an expression vector.
Lentiviral expression vector
The expression vector used is a lentiviral vector.
Additional optional microRNAs encoded by the engineered cells
Each cell further comprises a polynucleotide encoding a microRNA selected from miR-93-3p, miR-1260b, miR-767-5p, miR-30b-5p, miR-9-3p, and miR-9-5p.
Overall claim coverage centers on genetically engineered glial progenitor cells expressing at least one selected microRNA from the specified group, with optional additional microRNAs, and further scope defined by promoter types and expression vector format, including lentiviral vectors.
Stated Advantages
Suppressing signaling pathways STAT3, E2F6, and MAX.
Rejuvenation of adult glial progenitor cells.
Rejuvenation of adult CNS glial progenitor cells.
Treatment of myelin deficiency.
Treating myelin deficiency in the CNS.
Use of an in vivo chimeric mouse model with CBh-driven BCL11A lentivirus reporting increased proliferation and expansion of BCL11A-expressing GPC lineage and increased myelinating morphology without tumors.
Documented Applications
Rejuvenation of adult glial progenitor cells.
Treatment of myelin deficiency.
Treating myelin deficiency in the CNS using microRNA-/nucleic-acid-based rejuvenation of adult glial progenitor cells, including oligodendrocyte progenitor cells and NG2 cells.
Use of an in vivo chimeric mouse model with CBh-driven BCL11A lentivirus reporting increased proliferation and expansion of BCL11A-expressing GPC lineage and increased myelinating morphology without tumors.
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