Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Animal or plant cell
Reexamination Certificate
1998-06-17
2001-07-03
Clark, Deborah J. R. (Department: 1633)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Animal or plant cell
C424S093100
Reexamination Certificate
active
06254865
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods and compositions for transplantation of neurons. In particular, the present invention provides methods and compositions for the transplantation of terminally differentiated neurons derived from cell lines for the treatment of Huntington's disease and other neurological disorders.
BACKGROUND OF THE INVENTION
The clinical management of numerous neurological disorders has been frustrated by the progressive nature of degenerative, traumatic, or destructive neurological diseases and the limited efficacy and serious side-effects of available pharmacological agents. Conditions such as Huntington's disease, Alzheimer's disease, severe seizure disorders (e.g., epilepsy and familial dysautonomia), as well as injury or trauma to the nervous system have eluded most conventional pharmacological attempts to alleviate or cure the conditions.
Huntington's disease has proven particularly elusive to conventional pharmacological treatments. Huntington's disease is a progressive degenerative disease of the basal ganglia that is inherited as an autosomal dominant trait. The onset of Huntington's disease, an autosomal dominant, neurodegenerative disorder occurs at an average age of 35 to 40 years but can occur in persons as young as two years old or as old as 80 years (
Scientific American, Medicine
, Dale & Federman, eds. Vol. 3, 11(XV), p. 12-13 [1997]9(IV), p. 29 [1996]). The onset is insidious and is characterized by abnormalities of coordination, movement, and behavior. Movement abnormalities include restlessness, mild postural abnormalities, and quick jerking movements of the fingers, limbs, and trunk. The movement abnormalities may be accompanied by substantial weight loss. Depression is common, and cognitive abnormalities and inappropriate behavior may develop. In contrast to the choreic movements typical of onset in adults, juvenile patients may exhibit rigidity, tremor, and dystonia. In the course of eight to 15 years, the disorder progresses to complete incapacitation, with most patients dying of aspiration pneumonia or inanition.
In 1983, Huntington's disease became the first major inherited disorder with an unidentified basic defect to be linked with a DNA marker (Gusella et al., Nature 306:234 [1983]). The product of this gene, designated huntingtin, contains more than 3000 amino acids and is encoded by 10,366 bases at 4p16.3 (Huntington's Disease Collaborative Research Group, Cell 72:971 [1993]). Although knowledge of the underlying molecular basis for Huntington's disease has increased in recent years, pharmacological treatments based on this molecular knowledge have been limited to alleviating some of the symptoms associated with HD, a procedure that does not address the primary degenerative process nor the nonmotor aspects of the disease.
Cell therapy presents an alternative to these ineffective conventional pharmacological strategies for the treatment of neurological diseases. The goal of cell therapy is to replace, repair, or enhance biological function in damaged or deficient tissues or organs. Cell therapy is accomplished by the transplantation of isolated and characterized cells into a target tissue or organ in sufficient number and quality to restore or impart the desired function. Cell therapy, thus, provides a means of treating disorders where whole or partial organ transplantation is not practical or possible.
Cell transplantation methods have been of particular interest in the treatment of neurological diseases. However, mature neural tissues cannot be used for neural cell transplantation. Such tissues are not capable of surviving or establishing neurological function, which often depends on complex intercellular connections that cannot be surgically established. Thus, it is clear that improved methods and compositions are needed for the effective treatment of neurological diseases.
SUMMARY OF THE INVENTION
The present invention relates to methods and compositions for transplantation of neurons. In particular, the present invention provides methods and compositions for the transplantation of terminally differentiated neurons derived from cell lines for the treatment of Huntington's disease and other neurological disorders. In some embodiments, the present invention provides hNT neurons for transplantation into humans to treat Huntington's disease and other neurological disorders. In other embodiments, the present invention provides animals models for Huntington's disease.
The present invention provides a method for treating defective tissues comprising the steps of: 1) providing a plurality of hNT neurons and a neurologically defective mammal having a target tissue, wherein the target tissue comprises defective cells; and 2) transplanting the plurality of hNT neurons into the mammal under conditions such that a neurological defect of the mammal is ameliorated. In some embodiments, the present invention includes, but is not limited to, encapsulation of the hNT neurons prior to transplantation to reduce immunological response in the host.
In some embodiments, the hNT neurons comprise one or more heterologous nucleic acid sequences. The present invention is not limited to any particular heterologous nucleic acid. Appropriate heterologous nucleic acid sequences include, but are not limited to, nucleic acid sequences encoding a factor useful in ameliorating a defect in the transplant host (e.g., encoding one or more neuropeptide for the treatment of neurological disorders).
In certain embodiments of the present invention, the target tissue of the host comprises tissue of the central nervous system. All tissues of the central nervous system are contemplated by the present invention including, but not limited to, tissues of the brain and spinal cord. In preferred embodiments, the tissue of the central nervous system comprises tissue of the corpus striatum.
In preferred embodiments of the present invention, the host mammal is a human. In other preferred embodiments, the neurological defect comprises a neurological disorder. In particularly preferred embodiments, the neurological disorder is Huntington's disease.
The present invention also provides a method for treating Huntington's disease in a host, comprising transplanting a plurality of hNT neurons into a target tissue of the host. In some embodiments, the hNT neurons comprise one or more heterologous nucleic acid sequences, although the present invention is not limited to hNT neurons that comprises a heterologous nucleic acid sequence. In preferred embodiments of the present invention, the target tissue comprises tissue of the central nervous system. In particularly preferred embodiments, the tissue of the central nervous system comprise tissue of the corpus striatum.
The present invention further provides a non-human mammal having lesions of the corpus striatum and one or more tissues comprising transplanted hNT neurons. In some embodiments, the non-human mammal is selected from the order Rodentia. In particular embodiments, the non-human mammal is selected from the group consisting of mice and rats. In preferred embodiments, the one or more tissues comprising transplanted hNT neurons comprise one or more tissues of the central nervous system. In particularly preferred embodiments, the one or more tissues of the central nervous system comprise tissue of the corpus striatum. In some embodiments, the transplanted hNT neurons comprise one or more heterologous nucleic acid sequences, although the present invention is not limited to hNT neurons that comprise a heterologous nucleic acid sequence.
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patent: 5084350 (
Freed Curt R.
Kaddis Farida G.
Clark Deborah J. R.
Medlen & Carroll LLP
University Technology Corporation
Wilson Michael C.
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