Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-08-06
2002-04-23
Lankford, Jr., Leon B. (Department: 1651)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C424S179100, C424S183100, C424S570000
Reexamination Certificate
active
06376460
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to a method of modulating neuron cellular activity and agents useful for same. More particularly, the present invention contemplates inducing the apoptosis of neurons. Even more particularly, the present invention provides a method of inducing the apoptosis of specific sub-populations of neurons by administering an apoptosis inducing agent fused, linked or otherwise associated with a neuronal tracer. The method of the invention is useful, inter alia, in a variety of therapeutic or prophylactic applications.
BACKGROUND OF THE INVENTION
Bibliographic details of the publications numerically referred to in this application are collected at the end of the description.
Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated integer or step or groups of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
Identifying “magic bullets”, chemicals that will cure disease without causing major side effects, has always been a major goal of clinical medicine. One avenue for producing magic bullets for a variety of diseases was opened by the purification of ricin from castor oil seeds. Kabat E E, et al.,
J. Biol. Chem.,
168:629 (1947). Ricin destroys a cell's ability to make proteins by binding to and inactivating ribosomes, an essential component of the cell's protein synthetic machinery. Lin J Y, et al.,
Cancer Res.
31:921 (1971); Sperti S, et al.,
Biochem J.,
136:813 (1973). Because the cell cannot make protein, it dies over hours to days through apoptotic mechanisms. Bolognesi, et al.,
Int. J. Center.,
68:349 (1996). Ribosomal inactivating proteins (RIP's) with a similar activity to ricin have been isolated from a number of different plants (for example, abrin, saporin, modeccin). Although it was shown as early as 1970 that ricin was capable of killing tumor cells, RIP's were not immediately enlisted for therapeutic use in humans. Lin J-Y, et al.,
Nature,
227:292 (1970). The problem was one of targeting and specificity. RIP's could be internalized by many different kinds of cells and were often lethal to animals at low doses.
A major step toward the application of RIP's to the treatment of human disease came with the linking of ricin molecules that allowed the toxin to be targeted to a precisely defined population of cells in the body. The first agents used to target RIP's were antibodies that recognized and bound to proteins on certain types of cancer cells. Moolten F, et al.,
Ann. N.Y. Acad. Sci.,
277:690 (1976). Ligands that bound to specific types of cell surface receptors were also rapidly adopted as a means of getting RIP's into cells. Oeltmann T N, et al.,
J. Clin. Oncol.,
254:1028 (1979). These advances led to an explosion in the investigation of the uses of cell type—specific toxins based on the RIP's, ricin and saporin; and human trials have already occurred by antibody—linked RIP's (immunotoxins”) designed to eliminate certain types of cancer cell. See e.g., Lynch T J Jr, et al.,
J. Clin. Oncol.,
15:723 (1997); Engert A, et al.,
Blood,
89:403 (1997).
Treatment or cure of neurological problems that are caused by permanent dysfunction or excessive activation of populations of nerve cells are goals for RIP therapy. For these types of problems, drug treatments and surgery often provide only partial or transient solutions. For example, intramuscular injections of botulinum toxin, which are used to treat disorders characterized by involuntary muscle spasms, work for only a short time and muscle fibers eventually become resistant to the action of the toxin. Treatment of chronic pain often involves pain-killing drugs that become decreasingly effective with time and requires surgery to implant catheters to deliver the drugs directly into the space around the spinal cord. In these cases, as in many others, killing the dysfunctional or overactive nerve cells could permanently relieve or cure the clinical problem.
Despite the therapeutic appeal of killing nerve cells, RIP's have not been extensively assessed for their clinical potential in neurology. The reasons for this include the types of nerve cells that can currently be specifically and selectively killed by RIP-based neurotoxins and their methods of delivery. Ricin injected into the blood stream has been shown to kill nerve cells that lie outside the central nervous system, Wiley RG, et al.,
Brain Res.,
438:148 (1983), but not central neurons; and, when injected into the brain, ricin causes non-specific damage, killing large numbers of neurons at the site where it is injected. See e.g., Health PR, et al.,
Exp. Neurol.,
147:192 (1997).
To achieve more precise targeting of RIP-based neurotoxins, antibodies that recognize proteins on the surfaces of nerve cells have been linked to saporin and these immunotoxins have been shown to eliminate specific subsets of brain neurons. Effective immunoneurotoxins include
saporin linked to an antibody directed against the low affinity receptor for nerve growth factor (IgG192-saporin) which kills central cholinergic neurons, Book AA, et al.,
Brain Res.,
590:350 (1992), and
saporin linked to anti-dopamine &bgr;-hydroxylase, an enzyme required for the synthesis of some catacholamine neurotransmitters which kills noradrenergic neurons. Picklo M J, et al.,
Brain Res.,
195 (1994).
Neurotoxins have also been made from saporin and ligands that bind to specific types of receptors that occur on nerve cells, such as
Substance P-saporin, which binds to the neurokinin-1 receptor and kills a subset of dorsal horn neurons involved in processing information about painful stimuli. Mantyh P W, et al.,
Science.
278:275 (1997).
Currently, immunoneurotoxins and receptor ligand-based neurotoxins must be either injected directly into brain tissue or introduced into the ventricles of the brain or the intrathecal space around the spinal cord so that the toxin can gain access to the susceptible nerve cells via the cerebrospinal fluid.
Accordingly, there is a need to expand the currently limited accessibility of neurotoxin therapy to populations of neurons. For example, the range of currently accessible neuron types needs to be expanded to include a larger range of clinically relevant cell types. Further, there is a need to develop less invasive methods for exposing neurons to neurotoxic agents.
SUMMARY OF THE INVENTION
The present invention is directed to methods for delivering neurotoxins to neurons. The methods include the utilization of retrograde neuronal tracers which permit access to an expanded range of neuron types, via the periphery, which is a less invasive route of administration. Further, the use of neuron tracers also permits the delivery of neurotoxins to selective sub-populations of neurons.
Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
One aspect of the invention provides a method of modulating neuron cellular activity in a subject comprising administering to the subject an effective amount of an agent linked, fused or otherwise associated with a neuronal tracer wherein the tracer links, fuses or otherwise associates with the neuron and facilitates the transportation of the agent to the cell body of the neuron whereby the agent can modulate the cellular activity of the neuron.
Another aspect of the invention provides a method of modulating neuron cellular activity in a subject, comprising peripherally administering to the subject an effective amount of an agent linked, fused or otherwise associated with a neuronal tracer wherein the tracer links, fus
Flinders Technologies Pty. Ltd.
Flood Michele C.
Lankford , Jr. Leon B.
Merchant & Gould P. C.
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