Method of treating neurological disorders using long non-coding RNAs
Inventors
Cooper, Denise R. • Borlongan, Cesario • Bickford, Paula Cole • Patel, Niketa A. • Gould, Lisa
Assignees
US Department of Veterans Affairs • University of South Florida St Petersburg
Publication Number
US-9822359-B1
Publication Date
2017-11-21
Expiration Date
2035-01-22
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Abstract
A method of treating traumatic brain injury (TBI) and other neurological disorders is presented herein. Both conditioned media (CM) containing long non-coding RNAs such as NEAT1 (nuclear enriched abundant transcript 1) and MALAT1 (metastasis associated lung adenocarcinoma transcript 1) as well as human adipose-derived stem cells (hADSCs) themselves (Tx), when administered at least 3 hours post injury, were found to significantly ameliorate motor and cognitive functions in young, but not aged, mice undergoing TBI. Significant reduction in cortical damage and hippocampal cell loss was observed in both Tx and CM groups in young rats, whereas less neuroprotection was detected in the aged rats and mainly in the Tx group but not the CM group, which may in part result from decreased homing of the cells to the spleen.
Core Innovation
The invention presents a method of treating traumatic brain injury (TBI) and other neurological disorders by administering long non-coding RNAs (lncRNAs), specifically NEAT1 and MALAT1, via adipose-derived stem cells (hADSCs), conditioned media (CM) containing these lncRNAs, or direct gene delivery. The treatment, administered at least 3 hours post injury, significantly ameliorates motor and cognitive functions in young mice after TBI, and reduces cortical damage and hippocampal cell loss, but shows less neuroprotection in aged mice.
The method focuses on the role of secreted lncRNAs, such as NEAT1 and MALAT1, as part of the therapeutic effect of hADSCs through mechanisms like mRNA splicing, migration, and gene expression regulation. The inventors found that silencing these lncRNAs in conditioned media diminishes therapeutic efficacy, indicating their key role. The inventive approach also explores the biodistribution and homing of transplanted hADSCs, noting age-dependent differences especially in migration to the spleen, which may impact treatment outcomes.
The problem addressed arises from the need for effective regenerative therapies for neurological disorders such as TBI, which cause motor and cognitive impairments exacerbated by secondary cell death. Existing stem cell therapies have limited effectiveness in aged subjects, possibly due to reduced survival and altered migration of transplanted cells. The invention proposes methods leveraging stem cells and their secreted lncRNAs to improve neuroprotection, cognition, and recovery after TBI, especially highlighting the age-dependent therapeutic response and the mechanism involving lncRNAs.
Claims Coverage
The patent includes five claims, with independent claims 1, 3, and 4 describing methods involving administration of lncRNAs for treating traumatic brain injury and associated symptoms.
Method of treating traumatic brain injury using long non-coding RNAs
Administering a therapeutically effective amount of lncRNAs NEAT1 and MALAT1 to a patient using adipose-derived stem cells (ADSCs) lacking endothelial markers or conditioned media from cultured ADSCs to treat traumatic brain injury.
Method of improving cognition in traumatic brain injury patients
Administering therapeutically effective NEAT1 and MALAT1 lncRNAs intravenously in ADSCs lacking endothelial markers or conditioned media from cultured ADSCs to improve cognition in patients with traumatic brain injury.
Method of inducing neuroprotection in traumatic brain injury patients
Administering therapeutically effective NEAT1 and MALAT1 lncRNAs in ADSCs lacking endothelial markers or conditioned media from cultured ADSCs to induce neuroprotection in patients with traumatic brain injury.
The independent claims cover methods utilizing therapeutically effective amounts of lncRNAs NEAT1 and MALAT1, delivered via adipose-derived stem cells or their conditioned media, administered intravenously to treat traumatic brain injury, improve cognition, and induce neuroprotection.
Stated Advantages
Administration of adipose-derived stem cells or conditioned media containing lncRNAs significantly ameliorates motor and cognitive impairments associated with traumatic brain injury in young subjects.
The treatment reduces cortical damage and hippocampal cell loss, providing neuroprotection especially in young animals.
Long non-coding RNAs, particularly NEAT1 and MALAT1, secreted by stem cells are identified as a key mechanism mediating therapeutic efficacy.
The method provides a promising therapeutic intervention for traumatic brain injury with potential for improving functional recovery.
Documented Applications
Treatment of traumatic brain injury (TBI) using long non-coding RNAs, adipose-derived stem cells, or conditioned media.
Use for related neurological disorders such as stroke, ischemia, Huntington's disease, Alzheimer's disease, and Parkinson's disease.
Improvement of cognition and induction or enhancement of neuroprotection in patients with neurological disorders.
Use of long non-coding RNAs as biomarkers for diagnosis, prognosis, treatment efficacy, and monitoring progression of traumatic brain injury and related neurological disorders.
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