Use of stem cells expressing mesenchymal and neuronal markers and compositions thereof to treat neurological disease
Inventors
Kerkis, Irina • Valverde Wenceslau, Cristiane
Assignees
Fundaao Butantan • Fundacao Butantan • Avita International Ltd
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Publication Number
US-12239670-B2
Publication Date
2025-03-04
Expiration Date
Abstract
The invention provides pharmaceutical compositions comprising human immature dental pulp stem cells (hIDPSCs) wherein the hIDPSCs express CD44 and CD13. The invention also provides methods of treating a neurological disease or condition comprising systemically administering to a subject a pharmaceutical composition comprising hIDPSCs wherein the hIDPSCs express CD44 and CD13. For example, for treating neurological diseases or conditions including supporting the neuro-protective mechanism in subjects diagnosed with early HD or repairing lost DA neurons in subjects diagnosed with PD.
Core Innovation
The invention relates to treating neurodegenerative conditions by systemically administering a pharmaceutical composition comprising human immature dental pulp stem cells (hIDPSCs) that express CD44 and CD13. The hIDPSCs are administered systemically to a subject and are directed to central nervous system effects, including neuronal growth and repair, reduction of neuronal loss, and increased expression of neurotrophic and neuronal phosphoprotein-related factors in the CNS.
The disclosure states that the cells cross the blood-brain barrier and home to injured regions, including striatum, subventricular zone, and cortex. It further describes promotion of neurogenesis, including dopamine-associated neurogenesis markers such as DARPP-32 and dopamine receptor D2-related changes, together with neuroprotection via elevated neurotrophic factor secretion, particularly BDNF.
The described phenotype includes expression of CD44 and CD13 while lacking CD146 and, optionally, HLA-DR and HLA-ABC. The preclinical work in a 3-NP HD rat model with intravenous administration is summarized as showing histological engraftment, differentiation toward mature GABAergic spiny neurons, marker changes including DARPP-32, D2, and BDNF, and reported functional and survival/weight outcomes.
Claims Coverage
The independent claims cover three related treatment purposes using hIDPSCs with a defined marker expression profile: treating a neurodegenerative condition, promoting neuronal growth and repair and/or reducing neuronal loss in the CNS, and increasing expression of DARPP-32, dopamine receptor D2, BDNF, or combinations thereof in the CNS. The inventive features center on CD44 and CD13 expression, with additional phenotype constraints and delivery mode limitations in dependent claim sets.
Systemically treating neurodegenerative conditions with CD44 and CD13-positive hIDPSCs
Systemically administering to a subject a pharmaceutical composition comprising hIDPSCs, wherein the hIDPSCs express CD44 and CD13.
CNS neuronal growth and repair with CD44 and CD13-positive hIDPSCs
Administering to the subject a pharmaceutical composition comprising hIDPSCs, wherein at least 90% of the hIDPSCs express CD44 and CD13 to promote neuronal growth and repair, reduce neuronal loss, or both in the central nervous system (CNS).
Increasing DARPP-32, dopamine receptor D2, and/or BDNF using CD44 and CD13-positive hIDPSCs
Administering to the subject a pharmaceutical composition comprising hIDPSCs, wherein at least 90% of the hIDPSCs express CD44 and CD13 to increase expression of dopamine- and cAMP-regulated neuronal phosphoprotein (DARPP-32), dopamine receptor D2, brain-derived neurotrophic factor (BDNF), or combinations thereof in the central nervous system (CNS).
Across the independent claims, the inventive core is the systemic administration of a pharmaceutical composition comprising hIDPSCs defined by CD44 and CD13 expression, including embodiments requiring at least 90% CD44/CD13-positive cells. The claim set further ties therapeutic effect to CNS neuronal growth and repair, reduced neuronal loss, and increased expression of DARPP-32, dopamine receptor D2, and BDNF, with dependent refinements including absence of CD146 and optionally HLA-DR and HLA-ABC.
Stated Advantages
Promotes neurogenesis.
Provides neuroprotection via elevated neurotrophic factor secretion, especially BDNF.
Crosses the blood-brain barrier (BBB) and homes to injured regions including striatum/SVZ.
Increases or produces dopamine-associated neuronal outcomes, including DARPP-32 and dopamine receptor D2-related changes.
Designed anti-immunogenicity through absence of specified HLA markers and omission of certain marker expression profiles.
Reported preclinical improvements including functional and survival/weight outcomes in the 3-NP HD rat model.
Improved overall survival in the model.
Attenuation of 3-NP-associated weight loss.
Safety finding of fewer deaths and no additional deaths after repeated hIDPSC dosing in the model.
Documented Applications
Treating neurodegenerative conditions, including Huntington's disease (HD).
Promoting neuronal growth and repair and/or reducing neuronal loss in the CNS.
Increasing expression of DARPP-32, dopamine receptor D2, and BDNF in the CNS.
Preclinical work in a 3-nitropropionic acid (3-NP) HD rat model with intravenous administration of labeled hIDPSCs.
Use of hIDPSCs in a 3-nitropropionic acid (3-NP) rat model of Huntington’s disease (HD), including BBB crossing and striatum/cortex targeting with differentiation toward mature GABAergic spiny neurons.
Short- and long-term BDNF immunohistochemistry after systemic hIDPSC administration.
Veterinary CDV disease treatment observations.
Manufacturing and safety assessment elements for CELLAVITA™.
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