Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
1998-10-23
2003-04-22
Nguyen, Dave T. (Department: 1633)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S468000, C424S469000, C424S486000, C435S320100, C435S091400, C435S455000, C514S04400A
Reexamination Certificate
active
06551618
ABSTRACT:
TECHNICAL FIELD
The present invention relates generally to the treatment of neurons following NS injury that may result from surgery, trauma, compression, contusion, transection or other physical injury, from vascular pharmacologic or other insults including hemorrhagic or ischemic damage or from neurodegenerative or other neurological diseases. More specifically, the invention relates to the preparation and use of devices for transferring neuronal therapeutic agents and/or DNA encoding neuronal therapeutic agents into the NS, including devices that are gene activated matrices, to alter the function, gene expression or viability of neuronal cells therapeutically. The invention further relates to administration of such devices, including administration of matrices containing useful genes.
BACKGROUND OF THE INVENTION
Neuronal regeneration and restoration of neural connectivity within denervated tissues may be desirable events following acute or chronic nervous system (NS) injury resulting from physical transection/trauma, contusion/compression or surgical lesion, vascular pharmacologic insults including hemorrhagic or ischernic damage, or from neurodegenerative or other neurological diseases. Promotion of NS neuronal protection, neuronal survival and axon generation are well controlled processes that mainly originate during embryonic development and may persist through adulthood.
The stability of neuronal networks depends in part on the availability of a variety of specific architectural and biochemical cues in the neuronal environment that maintain neuronal projections, including axons. In the adult NS, the viability of neurons is maintained by the continuous retrograde flow of neurotrophic factors from the distal neuronal target to the neuronal cell body (perikaryon). Interruption of neural connections by physical severance of axons disconnects neuron from target and threatens neuronal survival.
Because of the spatiotemporal regulation of cues, including neurotrophic factors, essential for the maintenance of neural networks, axonal regrowth following NS injury is impaired by the absence of one or more appropriate stimuli in the vicinity of the damaged neuron. For example, neurotrophins (NT, discussed below) may be primary determinants of neuronal regeneration, and neurotrophin availability can be a primary limiting factor for axonal regrowth. Damaged neurons may initially start to regenerate axons, as a response to transient and regulated increases in the expression of neurotrophic factors, but regrowth is usually aborted within 14 days as intracellular stores of neurotrophin in the perikaryon are exhausted. Regrowth may also be inhibited in part by the deposition of fibrotic scar tissue during the course of wound healing. The synthesis and release of growth factors by mesenchymal and glial cells within the fibrotic scar may create localized microenvironments, or “sinks”, having high growth factor concentrations. Because neurotrophin dependent axonal regeneration obligatory proceeds up a concentration gradient of the neurotropic factor, axonal entrapment within a growth factor sink may result. Following axonal injury, a neuron may be deprived of essential maintenance signals (e.g., neurotrophic factors that ordinarily would be supplied from distal target regions through an intact axon), and may die. Consequently, reconnection of neural pathways is prevented and functional recovery may be compromised.
Efforts to induce axonal regrowth following NS injury have included direct or indirect administration of neurotrophic compounds at or near lesion sites. According to such approaches, a neurotrophic compound may be directly applied at or near a lesion, or may be indirectly introduced to the damaged tissue by a transplanted cell secreting the neurotrophin(s). These methods often produce localized sinks of high neurotrophin concentration at the lesion site in which axons may become entrapped. Thus, axonal extension beyond the lesion and along the damaged projection tracts may be impossible. Failure to re-establish neural connections and the ensuring neuronal atrophy may result in complete loss of function.
Another approach designed to promote axonal regrowth after NS injury utilizes recombinant viral vectors to deliver therapeutic genes encoding neurotrophic factors. Depending on the viral vector construct and delivery vehicle used, such approaches may under certain circumstances, (i) elicit inappropriate antiviral immune responses, (ii) promote undesirable viral toxic effects, (iii) have limited efficacy due, for example, to inefficiency of genetically altered viral gene promoter sequences, (iv) be tumorigenic and/or (v) lack specificity regarding the cell type to which therapeutic genes are delivered. Poor targeting of such recombinant viral vectors to specific cell types, for example, may limit the value of such an approach and may establish localized accumulations of therapeutic gene products at the site of vector delivery, giving rise to the problems associated with localized growth factor sinks and axonal entrapment.
In view of these and other problems associated with neuroregenerative therapy, there is a compelling need for improved and more effective treatments that are free of the above disadvantages.
The present invention exploits the use of gene activated matrices that, when administered into a NS lesion site or along the axonal projection tract proximal to a lesion, deliver high amounts of nucleic acids encoding a desired neuronal therapeutic product by retrograde axonal transport to distant, targeted neuronal cell perikaryons without inducing localized sinks of active product that may lead to axonal entrapment, while providing other related advantages.
SUMMARY OF THE INVENTION
The compositions and methods of the present invention may be useful wherever neuronal regeneration and restoration of connectivity within neural networks is sought, for example following any acute or chronic NS injury resulting from physical transection/trauma, contusion/compression or surgical lesion, vascular pharmacologic insults including hemorrhagic or ischemic damage, or from neurodegenerative or other neurological diseases.
NS injury resulting from physical transection/trauma, vascular pharmacologic insults and/or neurological diseases may further include mechanical insult and may also include NS injury resulting from burns or other chemical exposure. Such exposure may include but need not be limited to exposure to toxic compounds such as carbon monoxide or other metabolic poisons, or exposure to free radicals, as may also accompany aging or contribute to the pathogenesis of neurodegenerative disease. For example, increased levels of reactive oxygen species may be present, and may correlate with sites of neurodegeneration, in diseases such as Alzheimer's disease, Parkinson's disease or Huntington's disease.
Interruption of neural connections may be a consequence of acute or chronic NS injury leading to physical severance of axons that threatens neuronal survival, as described above. Accordingly, the compositions and methods of the present invention may delay cell degeneration and cell death by restoring the continuous retrograde flow of neurotrophic factors, from distal neuronal targets to neuronal perikarya, that is essential for maintenance of neural networks.
A considerable amount of work has been directed to the development of biocompatible matrices for use in medical implants, including those specifically for connective tissue implantation such as in bone or wound healing. In context of the present invention, a matrix may be employed in association with the gene or DNA coding region encoding a neuronal therapeutic agent in order to easily deliver the gene to the site of NS injury. The matrix is thus a “biofiller” that provides a structure for the regulated regeneration of neuronal axons. Such matrices may be formed from a variety of materials presently in use for implanted medical applications.
According to the present invention, compositions and methods are provided for
Baird Andrew
Berry Martin
Gonzalez Ana Maria
Logan Ann
Nguyen Dave T.
Seed Intellectual Property Law Group PLLC
University of Birmingham
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