SVCT2 transporters expressed in blood brain barrier cells
AssigneeXenoPort, Inc.
InventorNoa Zerangue
Life of this patent
Estimating the term…
Abstract
SVCT2 is consistently expressed at high levels in brain microvessel endothelial cells. Disclosed herein are assays for determining whether a test material/molecule is a substrate for, and/or is actively transported by, the SVCT2 transporter, and therefore a candidate substrate for crossing the blood brain barrier. The assays are useful in screening for therapeutic, cytotoxic or imaging compounds used in the treatment or diagnosis of neurological diseases.
Claims35
A method of screening an agent, conjugate, or conjugate moiety for activity useful for treating or diagnosing a disease, comprising:
- (a) providing a cell expressing the SVCT2 transporter, the transporter being situated in the plasma membrane of the cell;
- (b) contacting the cell with an agent, conjugate, or conjugate moiety;
- and
- (c) determining whether the agent, conjugate, or conjugate moiety passes through the plasma membrane via the SVCT2 transporter, passage through the SVCT2 transporter being useful for treatment or diagnosis of the disease;
- wherein:
- if step (b) comprises contacting the cell with the agent, the agent is a neuropharmaceutical agent or an imaging component;
- if step (b) comprises contacting the cell with the conjugate, the conjugate comprises an agent that is a neuropharmaceutical agent or an imaging component;
- or
- if step (b) comprises contacting the cells with the conjugate moiety, the method further comprises linking the conjugate moiety to an agent that is a neuropharmaceutical agent or an imaging component.
Use of the SVCT2 transporter to identify an agent or conjugate that is a substrate for the transporter and can cross the blood brain barrier and can therefore treat a CNS disease.
A pharmaceutical composition comprising a neuropharmaceutical agent or an imaging component linked to a conjugate moiety to form a conjugate, wherein the conjugate has a higher Vmax for SVCT2 than the neuropharmaceutical agent or the imaging component alone.
A method of screening an agent, conjugate, or conjugate moiety for capacity to be transported into the brain, comprising:
- (a) determining whether the agent, conjugate, or conjugate moiety specifically binds to the SVCT2 transporter;
- and
- (b) contacting the agent to one side of a polarized monolayer of brain microvessel endothelial cells;
- and
- (c) determining whether the agent is transported across the polarized monolayer.
A method of formulating a conjugate, comprising:
- (a) linking a neuropharmaceutical agent or imaging component to a conjugate moiety to form the conjugate, wherein the conjugate has a greater Vmax for the SVCT2 transporter than the neuropharmaceutical agent or imaging component alone;
- and
- (b) formulating the conjugate with a pharmaceutical carrier as a pharmaceutical composition.
A method of delivering a conjugate, comprising administering to a patient a pharmaceutical composition comprising a neuropharmaceutical agent or imaging component linked to a conjugate moiety to form the conjugate, wherein the conjugate has a higher Vmax for the SVCT2 transporter than the neuropharmaceutical agent or imaging component alone.
A method of screening an agent or imaging component for decreased side effects in the central nervous system (CNS), comprising:
- (a) providing
- (i) an agent having a pharmacological activity, wherein the pharmacological activity is useful for treating a disease present in a tissue other than the CNS, and the agent causes undesired side effects in the CNS if the agent enters the CNS;
- or
- (ii) an imaging component useful for imaging a tissue other than the CNS, and the imaging component causes undesired side effects in the CNS if the imaging component enters the CNS;
- (b) modifying the agent or imaging component;
- (c) providing a cell expressing at least one SVCT2 transporter protein that transports substrates across the blood brain barrier,
- (d) contacting the cell with the modified agent or modified imaging component;
- and
- (e) determining whether the modified agent or modified imaging component passes through the plasma membrane via the transporter protein with a lower Vmax than the agent, a lower Vmax indicating that the modification decreases the capacity of the modified agent or modified imaging component relative to the agent or imaging component to cross the blood brain barrier, thereby decreasing undesired side effects in the CNS.
Dependencies are inferred from the claim text.