Glymphatic delivery by manipulating plasma osmolarity
Inventors
Nedergaard, Maiken • Plog, Benjamin • Payne, Humberto Mestre
Assignees
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Publication Number
US-12311035-B2
Publication Date
2025-05-27
Expiration Date
Abstract
This invention relates to improving delivery of agents to the central nervous system.
Core Innovation
The invention relates to a CNS delivery strategy in which glymphatic system influx is enhanced by administering a hypertonic solution into plasma of a subject, followed by injecting an imaging/therapeutic composition into the central nervous system interstitium. The hypertonic solution comprises NaCl or Mannitol and is hypertonic with respect to the blood, and it is administered via intravenous, intraarterial, or intraperitoneal delivery.
After enhancing glymphatic system influx, the composition is injected intracisternally or intrathecally to the central nervous system interstitium, brain interstitium and/or the spinal cord interstitium. The disclosed approach emphasizes that hypertonicity markedly increases CSF tracer influx and distribution through perivascular glymphatic pathways without BBB disruption, and can override wake/AQP4-deficiency suppression.
The invention further includes transcranial macroscopic fluorescence imaging to quantify tracer influx and distribution, together with kit and article formats that combine a hyperglymphatic agent with the imaging/therapeutic composition. Supportive disclosures include validation of imaging, assessments of BBB permeability, intracranial pressure and interstitial fluid volume modeling, and anti-β plaque engagement results using disclosed plaque labeling.
Claims Coverage
The partial content identifies two independent claims, a delivery method and a neurological disorder treatment method. Each independent claim shares a two-stage sequence: enhancing glymphatic system influx with a hypertonic plasma solution, followed by intracisternal or intrathecal delivery to CNS interstitium.
Enhancing glymphatic system influx with hypertonic plasma NaCl or Mannitol
Enhancing glymphatic system influx by administering a hypertonic solution into plasma of the subject via intravenous, intraarterial, or intraperitoneal delivery, wherein the hypertonic solution comprises NaCl or Mannitol and is hypertonic with respect to the blood of the subject.
Intracisternal or intrathecal injection to CNS interstitium
Injecting the composition intracisternally or intrathecally to the central nervous system interstitium, brain interstitium and/or the spinal cord interstitium.
Treating a neurological disorder by combining hypertonic plasma influx enhancement and therapeutic intracisternal or intrathecal delivery
Treating a neurological disorder in a subject by enhancing glymphatic system influx by administering a hypertonic solution into plasma of the subject via intravenous, intraarterial, or intraperitoneal delivery, wherein the hypertonic solution comprises NaCl or Mannitol and is hypertonic with respect to the blood of the subject; followed by injecting a therapeutic composition intracisternally or intrathecally to the central nervous system interstitium, brain interstitium and/or the spinal cord interstitium.
Across the identified independent claims, the main inventive coverage is the combination of enhancing glymphatic system influx through administration of a hypertonic NaCl or Mannitol solution into plasma via intravenous, intraarterial, or intraperitoneal delivery, and subsequent intracisternal or intrathecal injection of an imaging/therapeutic or therapeutic composition to the central nervous system interstitium, including brain and/or spinal cord interstitium.
Stated Advantages
Hypertonicity markedly increases CSF tracer influx and distribution through perivascular glymphatic pathways without BBB disruption.
The approach can override wake/AQP4-deficiency suppression.
Improves delivery and target engagement of an anti-β antibody in an APP/PS1 mouse model.
Documented Applications
Improving delivery of an imaging/therapeutic composition to central nervous system interstitium, brain interstitium and/or spinal cord interstitium.
Treating a neurological disorder by combining hypertonic plasma glymphatic-influx enhancement with injection of a therapeutic composition intracisternally or intrathecally.
Use in connection with anti-β antibody delivery and plaque engagement in an APP/PS1 mouse model.
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