Methods and compositions for rejuvenating CNS glial populations by suppresion of transcription factors
Inventors
Goldman, Steven A. • Mariani, John N. • Benraiss, Abdellatif
Assignees
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Publication Number
US-12686868-B2
Publication Date
2026-07-21
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, an effective amount of an agent that suppresses one or more transcription factors selected from the group consisting of (i) zinc finger protein 274 (ZNF274), (ii) Myc-associated factor X (MAX), (iii) E2F transcription factor 6 (E2F6), (iv) zinc finger protein Aiolos (IKZF3), and (v) signal transducer and activator of transcription 3 (STAT3).
Core Innovation
The disclosure provides classes of small-molecule STAT3 and MAX inhibitors, including example compound names and structures, presented as transcription-factor inhibitors. The document further expands the inhibition concept to nucleic-acid inhibitors targeting transcription-factor-related genes and pathways, including ZNF274, MAX, E2F6, IKZF3, and STAT3.
The disclosed nucleic-acid inhibitors include miRNA, siRNA, shRNA, and antisense oligonucleotides. For nucleic-acid inhibition, the disclosure specifies miRNA/siRNA/shRNA/antisense approaches directed to the above targets, and includes example miRNA sequences.
The document further describes nucleic-acid gene-silencing using CRISPR-based nuclease systems, including Cas proteins and guide RNA concepts, and CRISPRi approaches using nuclease dead Cas with epigenetic fusions. It also discusses vector and regulatory elements, including glial-specific promoters and inducible systems such as Tet-on/Tet-off.
The disclosure outlines genetically modified glial progenitor cells and their study context, including adult glial progenitor cells and context related to myelin deficiency and rejuvenation of glial progenitor cells.
Claims Coverage
The independent claims cover at least three core inventive features: transcription-factor suppression of ZNF274 and/or E2F6 in adult glial progenitor cells, nucleic-acid-based Cas/guide RNA agent design with accession-defined targets and 5–100 nucleotide guide length, and suppression endpoints that include a senescence-associated gene expression signature (including CDKN1A/p21) and/or CDKN1A/p21 and CDKN2A/p16 expression in adult glial progenitor cells.
Suppressing a senescence-associated gene expression signature in adult glial progenitor cells
Administering an agent that suppresses one or more transcription factors selected from zinc finger protein 274 (ZNF274) and E2F transcription factor 6 (E2F6) to a population of adult glial progenitor cells, wherein the senescence-associated gene expression signature comprises CDKN1A/p21.
Cas protein and guide RNA agent targeting ZNF274 and/or E2F6
Providing an agent comprising one or more nucleic acid molecules that comprise a first nucleic acid sequence encoding a Cas protein and a second nucleic acid sequence encoding a guide RNA complementary to an E2F6 gene of Accession No: NM 001278277.2 or complementary to a ZNF274 gene of Accession No: XR 001753588.2, wherein the guide RNA is 5 to 100 nucleic acid residues in length.
Suppressing CDKN1A/p21 and/or CDKN2A/p16 expression in adult glial progenitor cells
Administering an agent that suppresses expression of either CDKN1A/p21 or CDKN2A/p16, or both, in a population of adult glial progenitor cells, wherein the agent suppresses one or more transcription factors selected from ZNF274 and E2F6.
Guide RNA complementary to transcription factor gene portions for p21/p16 suppression
Including, within the agent, one or more nucleic acid molecules comprising a first nucleic acid sequence encoding a Cas protein and a second nucleic acid sequence encoding a guide RNA complementary to a portion of a gene encoding one or more of the transcription factors, where the guide RNA is complementary to an E2F6 gene of Accession No: NM 001278277.2 or complementary to a ZNF274 gene of Accession No: XR 001753588.2, and where the guide RNA is 5 to 100 nucleic acid residues in length.
Across the independent claims, the coverage is directed to suppressing transcription-factor activity of ZNF274 and E2F6 in adult glial progenitor cells using Cas/guide RNA nucleic-acid agents with defined guide RNA lengths and accession-defined targets, resulting in repression of a senescence-associated gene expression signature (including CDKN1A/p21) and suppression of CDKN1A/p21 and/or CDKN2A/p16 expression.
Stated Advantages
Rejuvenating adult CNS glial progenitor cells.
Treating glial-cell disorders and myelin deficiency.
Suppressing senescence-associated gene expression signatures in adult glial progenitor cells.
Repressing or suppressing expression of CDKN1A/p21 and/or CDKN2A/p16 in adult glial progenitor cells.
Documented Applications
Treating glial-cell disorders.
Treating myelin deficiency.
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