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  Treatment of neurological deficits in the striatum or substanta nigra pars compactaUSPTO Application #: 20060069008Title: Treatment of neurological deficits in the striatum or substanta nigra pars compacta Abstract: The present invention is directed to methods of treating neurological deficits resulting from injury or disease to the striatum or substanta nigra pars compacta of a human by administering human recombinant GDF5 to the striatum or substanta nigra pars compacta of a human in amounts effective to induce cell populations having the capacity to differentiate towards a dopaminergic phenotype to in fact differentiate towards a dopaminergic phenotype, and to neurotrophic compositions and matrices suitable for use in such treatments. (end of abstract) Agent: Philip S. Johnson Johnson & Johnson - New Brunswick, NJ, US Inventors: Sanjay Mistry, Darin J. Messina USPTO Applicaton #: 20060069008 - Class: 514002000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai The Patent Description & Claims data below is from USPTO Patent Application 20060069008. Brief Patent Description - Full Patent Description - Patent Application Claims
FIELD OF INVENTION [0001] The present invention is directed to methods of treating neurological deficits resulting from injury or disease to the striatum or substanta nigra pars compacta of a human by administering human recombinant GDF5 thereto, and to compositions and matrices containing human recombinant GDF5 for use in such methods of treatment. BACKGROUND OF THE INVENTION [0002] No satisfactory method exists to repair the damage caused by neuropathies, such as may be attributable to Parkinson's disease (Parkinsonism) or stroke. Parkinson's disease is a syndrome consisting of neurological deficits such as tremor, rigidity, brady- and hypokinesia, and other deficits in equilibrium and posture. Parkinson's disease is often associated with the aging of the nervous system. Similarly, stroke can affect the motor system, rendering the patient with symptoms of hemiparesis or paralysis. [0003] The substantia nigra is the principal site of pathology in Parkinson's disease. [0004] Pigmented neurons of the substantia nigra project widely and diffusely to the caudate-putamen (corpus striatum) and are specialized to synthesize and release dopamine. Symptoms of Parkinsonism emerge when 75-80% of the dopaminergic innervation is destroyed. Patients with Parkinson's disease respond to dopamine replacement therapy. Unfortunately, the efficacy of dopamine replacement therapy decreases progressively with continued degeneration of the nigrostriatal dopaminergic pathway. [0005] The identification of stem cells has stimulated research aimed at the selective generation of specific cell types for regenerative medicine. Although protocols have been developed for the directed differentiation of stem cells into therapeutically relevant cell types, such as dopaminergic (DA) neurons for the treatment of Parkinson's, motor neurons for the treatment of ALS, and oligodendrocytes for the treatment of MS, the efficient generation of substantial numbers of these cell types from stem cells has not yet been reported. The ability to generate unlimited numbers of DA neurons that express the full complement of midbrain DA neuron markers is an important part to providing a cure for Parkinson's. Thus, agents that can be utilized to stimulate the differentiation of stem cells to the DA lineage provide a potential to harness and differentiate both exogenous and endogenous stem cells for Parkinson's as well as stokes affecting the middle cerebral artery (MCA) and its branches. [0006] In other cases, attempts to counteract the effects of acute or neurodegenerative lesions of the brain and/or spinal cord have primarily involved implantation of embryonic neurons in an effort to compensate for lost or deficient neural function. However, human fetal cell transplantation research is severely restricted. Administration of neurotrophic factors such as nerve growth factor and insulin-like growth factor also have been suggested to stimulate neuronal growth within the central nervous system (CNS). See, e.g., Lundborg, Acta Orthop. Scand. 58: 145-169 (1987); U.S. Pat. No. 5,093,317. Administration of neurotrophic factors to the CNS requires bypassing the blood-brain barrier. The parrier may be overcome by direct infusion, or by modifying the molecule to enhance its transport across the barrier, as by chemical modification or conjugation, or by molecule truncation. Many growth factors from the TGF-beta superfamily [Kingsley, Genes & Development 8 133-146 (1994)] and the literature cited therein are relevant for a wide range of medical treatment methods and applications which in particular concern wound healing and tissue regeneration. Some of these multifunctional proteins also have survival promoting effects on neurones in addition to functions such as regulation of the proliferation and differentiation in many cell types [Roberts and Sporn, Handbook of Experimental Pharmacology 95 419-472, eds. Sporn and Roberts (1990); Sakurai et al., J. Biol. Chem., 269 14118-14122 (1994)]. Thus for example trophic effects on embryonic motor and sensory neurones were demonstrated for TGF-beta in vitro [Martinou et al., Devl. Brain Res., 52 175-181 (1990); Chalazonitis et al., Dev. Biol., 152 121-132 (1992)]. In addition effects promoting survival were shown on dopaminergic neurones of the midbrain for the proteins TGF-beta-1, -2, -3, activin A and GDNF (glial cell line-derived neurotrophic factor), a protein which has structural similarities to TGF-beta superfamily members but these effects were not mediated via astrocytes [Krieglstein et al., EMBO J., 14, 736-742 (1995)]. The occurrence of proteins of the TGF-beta superfamily in various tissue and developmental stages corresponds with differences with regard to their exact functions as well as target sites, life-span, requirements for auxiliary factors, necessary cellular physiological environment and/or resistance to degradation. [0007] GDF5 is expressed in the neonatal rat midbrain, suggesting that it may play a role in the development of dopaminergic neurons [Krieglstein et al., J. Neurosci. Res., 42 724-32 (1995)]. In vitro studies have demonstrated that MP52 has survival-promoting actions on embryonic rat dopaminergic neurons protecting them against the toxin 1-methyl-4-pyridinium (MPP+). Moreover, in vivo studies have demonstrated that intraparenchymal injection of GDF5 protects the adult rat nigrostriatal dopaminergic system from death induced by 6-hydroxydopamine (60HDA) lesion of the medial forebrain bundle [Sullivan et al., Eur. J. Neurosci., 233 73-6 (1997)]. However, while such studies indicate that GDF5 appears to play important roles in the development and protection of the dopaminergic limbic system, they do not address or shed any light on the relevance of GDF5 with respect to neuroregenerative capacity or the ability to differentiate endogenous or exogenous cell populations. [0008] Accordingly, there is a need for treatment of neurological deficits resulting from injury or disease to the striatum or substanta nigra pars compacta of a human. The present invention seeks to utilize human recombinant GDF5 in a manner that enables the treatment or prevention of such resulting deficits. SUMMARY OF THE INVENTION [0009] The present invention is directed to methods of treating neurological deficits resulting from injury or disease to the striatum or substanta nigra pars compacta of a human comprising administering human recombinant GDF5 to the striatum or substanta nigra pars compacta of a human in amounts effective to induce cell populations having the capacity to differentiate towards a dopaminergic phenotype to in fact differentiate cells towards said dopaminergic phenotype, and to compositions and matrices comprising human recombinant GDF5 that are suitable for treating such deficits. DETAILED DESCRIPTION OF THE INVENTION [0010] Neurogenesis has been demonstrated in the adult hippocampus, subventricular zone, substantia nigra, and olfactory bulbs. Thus, agents that can recruit and/or differentiate these cells into DA specific neurons are essential for providing cell replacement in treating neurological deficits resulting from injury or disease to the striatum or substanta nigra pars compacta of a human that may be attributable to Parkinson' disease. In methods of treatment and compositions of the present invention, human recombinant GDF5 is utilized as a pre-differentiation or differentiation agent to differentiate stem or progenitor cell populations, whether endogenous or exogenous. The invention is based, at least in part, on the discovery that human recombinant GDF5 is a neurotrophic factor that selectively induces adult Neural hippocampal progenitor cells to differentiate towards a dopaminergic phenotype. The data described herein demonstrate that human recombinant GDF5 is a potent inducer of neural stem cell differentiation. These results thus demonstrate the synergistic utility of human recombinant GDF5 for providing neuroregenerative function, in addition to its neuroprotective function. [0011] GDF5 is a protein that functions as a growth and differentiation factor. The protein may be found in its natural state in mammals. Naturally occurring human GDF5 may be modified, purified or otherwise treated to form human recombinant GDF5, as further described herein and as those skilled in the art would understand. "Human recombinant GDF5" will be referred to generically herein as GDF5-HR. Known GDF5-HR proteins include BMP-14, CDMP-1 and MP52. [0012] MP52, available from Biopharm GmbH, a German corporation having a 10 place of business in Heielberg, Germany, was first isolated for its cDNA as an osteogenetic factor belonging to TGF-beta gene superfamily in 1994. MP52 is a protein having 120 amino acid residues with alanine at the N-terminus, and its amino acid sequence is reported in WO93/16099 and WO95/04819. It is evident from various animal tests that MP52 is involved in osteogenesis similar to other osteogenetic factors. [0013] Since MP52 has been discovered to be a potent inducer of neural stem cell differentiation, it has been determined that it would be useful for the treatment of neurological deficits in the striatum or substanta nigra pars compacta of a human attributable to neurodegenerative diseases, in particular Parkinson's, or damage caused by stokes affecting the middle cerebral artery (MCA) and its branches. While we have found that MP52 alone can stimulate the differentiation of adult neural progenitors isolated from the hippocampus towards a dopaminergic phenotype, it may be combined with agonists to induce enhanced dopaminergic differentiation in neural stem cells, or in other cells that have the capacity to differentiate towards a dopaminergic phenotype. For example, MP52 may be utilized in combination with Sonic Hedgehog (SHH) or Fibroblast Growth Factor 8 (FGF8), providing a significantly enhanced method for inducing neural stem cells and other cells described herein to become dopaminergic in phenotype. SHH is an integral part of the Wnt signaling pathway; the other factors important in this developmental pathway may be important for neuronal formation in combination with GDF5-HR. [0014] GDF5-HR could also be used to differentiate forms of stem cells other than adult neural progenitors, such as hippocampal progenitor cells or hippocampal stem cells, or other cells having the capacity to differentiate towards a dopaminergic phenotype. These other forms of cells include, but are not limited to, mesenchymal stem cells, hematopoietic stem cells, embryonic stem cells (ESCs), progenitors derived from embryonic stem cells, postpartum-derived stem or progenitor cells, cells derived from umbilical cord or placental tissue, muscle derived stem or progenitor cells, pancreatic-derived stem or progenitor cells, limbal-derived stem or progenitor cells, retinal-derived stem or progenitor cells, and liver-derived stem or progenitor cells. [0015] GDF5-HR may be used singly as a neurotrophic factor to induce cell populations to differentiate in the treatment of neurological deficits in the striatum or substanta nigra pars compacta of a human. The term neurotrophic, as used herein, is defined to include the potential to restore, regenerate and differentiate cells. Also, the protein may be incorporated into a neurotrophic composition or used in conjunction with a suitable matrix that acts as a delivery or support system. The neurotrophic composition will comprise an effective amount of GDF5-HR. By effective amount, it is meant that amount effective to induce cell populations comprising the capacity to differentiate towards a dopaminergic phenotype to in fact differentiate towards said dopaminergic phenotype. Neurotrophic compositions of the present invention may comprise about 0.5 to about 1,000 nanograms of MP52, or about 0.5 to about 200 nanograms of MP52. [0016] A neurotrophic composition may be obtained by fixing, mixing, dissolving or suspending the GDF5-HR in a pharmaceutically acceptable carrier or an aqueous solvent. For example, suitable examples of carriers or aqueous solvents include, but are not limited to, clinical grade sterile water, sterile saline, sterile phosphate buffered saline, dextrose in sterile water, sterile liquid media or other physiologically acceptable isotonic liquids. In addition, the neurotrophic composition of the present invention can contain a variety of pharmacologically acceptable additives, such as a stabilizer, a preservative, a thickener, a solubilizer and the like, which can be combined with the carrier or aqueous solvent. [0017] GDF5-HR may also be used in conjunction with a suitable matrix that acts as a delivery or support system. A successful matrix for a GDF5-HR desirably performs several important functions. It desirably binds the GDF5-HR and acts as a slow or sustained release delivery system, and accommodates each step of the cellular response during differentiation. The matrix would prevent diffusion of GDF5-HR from the site of delivery, thus localizing the effect of the GDF5-HR on the delivered cells. In addition, selected matrix materials should be biocompatible in vivo, porous and preferably biodegradable. The term biodegradable as used herein is defined to include materials that are degraded or broken down (chemically or physically) under physiological conditions in the body such that the degradation products are excretable or absorbable by the body. The biodegradation rate can vary according to the desired release rate once implanted in the striatum or substanta nigra pars compacta. The matrix desirably also acts as a temporary scaffold until replaced by newly grown neural tissue. Therefore, in one embodiment, the matrix provides for sustained release of the neurotrophic factor component to a patient in need of the factor and may provide a structure for developing tissue growth in the patient. The matrix can be in particulate form (macroparticles greater than 10 microns in diameter or microparticles less than 10 microns in diameter), or can be in the form of a structurally stable, three-dimensional implant (e.g., a scaffold). The implant can be, for example, a cube, cylinder, tube, block, film, sheet, or an appropriate anatomical form. [0018] Factors affecting the mechanical performance of in vivo biodegradable polymers are well known to the polymer scientist, and include monomer selection, initial process conditions, and the presence of additives. Biodegradation has been accomplished by synthesizing polymers that have unstable linkages in the backbone, or linkages that can be safely oxidized or hydrolyzed in the body. The most common chemical functional groups having this characteristic are ethers, esters, anhydrides, orthoesters and amides. Therefore, in one embodiment of the present invention, GDF5-HR is controllably released from the biodegradable polymer matrix to the site where it is needed by hydrolysis of chemical bonds in the biodegradable polymer. Biodegradable polymer matrices are preferably in the form of a powder, microparticle, microsphere, strip, gel, such as an in situ polymerizable gel, web or sponge. [0019] The biocompatible matrix may be comprised of natural, modified natural or synthetic biodegradable polymers, including homopolymers, copolymers and block polymers, as well as combinations thereof. It is noted that a polymer is generally named based on the monomer from which it is synthesized. [0020] Examples of suitable biodegradable polymers or polymer classes include fibrin, collagen, elastin, gelatin, vitronectin, fibronectin, laminin, reconstituted basement membrane matrices, starches, dextrans, alginates, hyaluron, chitin, chitosan, agarose, polysaccharides, hyaluronic acid, poly(lactic acid), poly(glycolic acid), polyethylene glycol, decellularized tissue, self-assembling peptides, polypeptides, glycosaminoglycans, their derivatives and mixtures thereof. For both glycolic acid and lactic acid, an intermediate cyclic dimer is typically prepared and purified prior to polymerization. These intermediate dimers are called glycolide and lactide, respectively. Other useful biodegradable polymers or polymer classes include, without limitation, polydioxanones, polycarbonates, polyoxalates, poly(alpha-esters), polyanhydrides, polyacetates, polycaprolactones, poly(orthoesters), polyamino acids, polyamides and mixtures and copolymers thereof. Additional useful biodegradable polymers include, without limitation stereopolymers of L- and D-lactic acid, copolymers of bis(para-carboxyphenoxy) propane acid and sebacic acid, sebacic acid copolymers, copolymers of caprolactone, poly(lactic acid)/poly(glycolic acid)/polyethyleneglycol copolymers, copolymers of polyurethane and (poly(lactic acid), copolymers of polyurethane and poly(lactic acid), copolymers of alpha-amino acids, copolymers of alpha-amino acids and caproic acid, copolymers of alpha-benzyl glutamate and polyethylene glycol, copolymers of succinate and poly(glycols), polyphosphazene, polyhydroxy-alkanoates and mixtures thereof. Binary and ternary systems also are contemplated. Continue reading... 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