US 2003/0083299 A1 · Non-invasive delivery of polypeptides through the blood-brain barrier

Abstract

A treatment method and genetic vectors are disclosed for non-invasive delivery of polypeptides through the blood brain barrier (BBB), to treat brain or spinal tissue. A genetic vector is used to transfect one or more neurons which “straddle” the BBB, such as sensory neurons, nocioceptive neurons, or lower motor neurons; this is done by administering the vector in a manner that causes it to contact neuronal projections that extend outside the BBB. Once inside a peripheral projection that belongs to a BBB-straddling neuron, the vectors (or some portion thereof) will be transported to the main cell body of the neuron, through a process called retrograde transport. Inside the main cell body, at least one gene carried by the genetic vector will be expressed, to form polypeptides. Some of these polypeptides (which can include leader sequences that will promote anterograde transport and secretion by BBB-straddling neurons) will be transported by the neurons to secretion sites inside the BBB. The polypeptides will be secreted by transfected neurons at locations inside the BBB, and will then contact and exert their effects upon secondary “target” neurons located entirely within the BBB. By using this system, polypeptides that stimulate nerve growth or activity can be used to treat neurodegenerative diseases, impaired limbs in stroke victims, etc., and polypeptides that suppress neuronal activity can be used to treat unwanted excessive neuronal activity, such as neuropathic pain. This approach also provides new methods for delivering endocrine and paracrine polypeptides into the CNS, thereby allowing improved medical and reproductive treatments in humans, and improved ability to modulate growth, maturation, reproduction, or other endocrine-related functions among livestock, endangered species, and other animals.

Claims47

Dependent claims

A method for delivering neuroactive polypeptide molecules through a blood-brain barrier in a higher animal, comprising the steps of:

a. creating a genetic vector which carries at least one gene which encodes a neuroactive polypeptide, and which is constructed in a manner which will enable the genetic vector to transfect at least one class of accessible neurons which straddle the blood-brain barrier, each such accessible neuron having at least one peripheral projection that is accessible to compounds that have not penetrated the animal's blood-brain barrier, if said genetic vector is administered to such higher animal by means which cause direct contact between at least one copy of the genetic vector and at least one such peripheral projection, wherein the gene which encodes the neuroactive polypeptide is capable of expressing copies of the neuroactive polypeptide within such accessible neurons after such accessible neurons have been transfected by said genetic vector;
and,
b. administering the genetic vector to the higher animal in a location and manner which ensure that:
(i) at least one copy of the genetic vector contacts and transfects at least one such accessible neuron;
and (ii) at least one such accessible neuron expresses the neuroactive polypeptide encoded by the gene and subsequently secretes the neuroactive polypeptide into central nervous system tissue which is protected by the blood-brain barrier.

2 more elements

A genetic vector designed to initiate and capable of initiating a neuronal process that will non-invasively deliver neuroactive polypeptide molecules into central nervous system tissue protected by a blood-brain barrier in a higher animal, said genetic vector comprising cell transfection components and associated genetic material, which have been assembled into a genetic vector which is suited for and capable of transfecting at least one type of accessible neuron which straddles the blood-brain barrier and has at least one peripheral projection that is accessible to genetic vectors that have not penetrated an animal's blood-brain barrier,

wherein:
a. the cell transfection components are selected to cause the genetic vector to (i) bind to the selected type of accessible neuron, and (ii) insert associated genetic material carried by the genetic vector into the accessible neurons;
and,
b. the associated genetic material contains at least one gene which encodes a neuroactive polypeptide, wherein said gene has a gene promoter that causes the gene to be expressed, inside transfected accessible neurons, into said neuroactive polypeptide or a precursor thereof, and wherein copies of the neuroactive polypeptide or precursor thereof have been shown to be (i) transported, within transfected accessible neurons, to neuronal secretion locations in central nervous system tissue that is protected by the blood-brain barrier of the animal, and (ii) secreted by transfected accessible neurons at such neuronal secretion locations, in central nervous system tissue that is protected by the blood-brain barrier of the animal.

1 more element

Dependencies are inferred from the claim text.

Non-invasive delivery of polypeptides through the blood-brain barrier

Life of this patent

Non-invasive delivery of polypeptides through the blood-brain barrier

Life of this patent

Abstract

Claims47