Chemistry: molecular biology and microbiology – Differentiated tissue or organ other than blood – per se – or...
Reexamination Certificate
1999-05-07
2003-03-04
Kunz, Gary (Department: 1647)
Chemistry: molecular biology and microbiology
Differentiated tissue or organ other than blood, per se, or...
C435S368000, C435S325000
Reexamination Certificate
active
06528245
ABSTRACT:
BACKGROUND
1. Field of Use
This application relates to methods of culturing bone marrow cells such that they express neuronal phenotype for use in transplantation.
2. Background Information
Neurobiologists have long considered the neurons in the adult brain to be like a precious nest egg: a legacy that dwindles with time and illness and is difficult if not impossible to rebuild. Parkinson's and Alzheimer's are examples of neurodegenerative diseases whose cures await scientists overcoming the difficulty of rebuilding neurons in the human adult brain. Parkinson's disease (PD), is a disorder of middle or late life, with very gradual progression and a prolonged course. HARRISON'S PRINCIPLES OF INTERNAL MEDICINE, Vol. 2, 23d ed., Ed. by Isselbacher, Braunwald, Wilson, Martin, Fauci and Kasper, McGraw-Hill Inc., New York City, 1994, pg. 2275. The most regularly observed changes have been in the aggregates of melanin-containing nerve cells in the brainstem (substantia nigra, locus coeruleus), where there are varying degrees of nerve cell loss with reactive gliosis (most pronounced in the substantia nigra) along with distinctive eosinophilic intracytoplasmic inclusions. (Id. at 2276).
In its fully developed form, PD is easily recognized. The stooped posture, the stiffness and slowness of movement, the fixity of facial expression, the rhythmic tremor of the limbs, which subsides on active willed movement or complete relaxation, are familiar to every clinician. Generally, accompanying the other characteristics of the fully developed disorder is the festinating gait, whereby the patient, prevented by the abnormality of postural tone from making the appropriate reflex adjustments required for effective walking, progresses with quick shuffling steps at an accelerating pace as if to catch up with the body's center of gravity. (Id. at 2276).
Although the modem treatment of PD is more successful than any that was available before the introduction of levodopa, including stereotactic surgery, there are still many problems. (Id. at 2277). Underlying much of the difficulty undoubtedly is the fact that none of these therapeutic measures has an effect on the underlying disease process, which consists of neuronal degeneration. Ultimately, a point seems to be reached where pharmacology can no longer compensate for the loss of basal ganglia dopamine. (Id.).
Alzheimer's Disease (AD) is due to a degenerative process characterized by progressive loss of cells from the basal forebrain, cerebral cortex and other brain areas. Acetylcholine-transmitting neurons and their target nerves are particularly affected. Senile plagues and neurofibrillary tangles are present. Pick's disease has a similar clinical picture to Alzheimer's disease but a somewhat slower clinical course and circumscribed atrophy, mainly affecting the frontal and temporal lobes. One animal model for Alzheimer's disease and other dementias displays hereditary tendency toward the formation of such plaques. It is thought that if a drug has an effect in the model, it also may be beneficial in at least some forms of Alzheimer's and Pick's diseases. At present there are palliative treatments but no means to restore function.
A group of degenerative disorders characterized by progressive ataxia due to degeneration of the cerebellum, brainstem, spinal cord and peripheral nerves, and occasionally the basal ganglia. Many of these syndromes are hereditary; other occur sporadically. The spinocerebellar degenerations are logically placed in three groups: predominantly spinal ataxias, cerebellar ataxias and multiple-system degenerations. To date there are no treatments. Friedrich's ataxia is the prototypical spinal ataxia whose inheritance is autosomal recessive. The responsible gene has been found on Chromosome 9. Symptoms begin between ages of 5 and 15 with unsteady gait, followed by upper extremity ataxia and dysarthria. Patients are areflexic and lose large-fiber sensory modalities (vibration and position sense). Two other diseases have similar symptoms: Bassen-Kornzweig syndrome (abeta-lipoproteinemia and vitamin E deficiency) and Refsom's disease (phytanic acid storage disease). Cerebellar cortical degenerations generally occur between ages 30 and 50. Clinically only signs of cerebellar dysfunction can be detected, with pathologic changes restricted to the cerebellum and occasionally the inferior olives. Inherited and sporadic cases have been reported. Similar degeneration may also be associated with chronic alchoholism.
In multiple-system degenerations, ataxia occurs in young to middle adult life in varying combinations with spasticity and extrapyramidal, sensory, lower motor neuron and autonomic dysfunction. In some families, there may also be optic atrophy, retinitis pigmentosa, opthalmoplegia and dementia.
Another form of cerebellar degeneration is paraneoplastic cerebellar degeneration that occurs with certain cancers, such as oat cell lung cancer, breast cancer and ovarian cancer. In some cases, the ataxia may precede the discovery of the cancer by weeks to years. Purkinje cells are permanently lost, resulting in ataxia. Even if the patient is permanently cured of the cancer, their ability to function may be profoundly disabled by the loss of Purkinje cells. There is no specific treatment.
Strokes also result in neuronal degeneration and loss of functional synapses. Currently there is no repair, and only palliation and rehabilitation are undertaken.
Neurotransplantation has been used to explore the development of the central nervous system and for repair of diseased tissue in conditions such as Parkinson's and other neurodegenerative diseases. The experimental replacement of neurons by direct grafting of fetal tissue into the brain has been accomplished in small numbers of patients in several research universities (including our University of South Florida); but so far, the experimental grafting of human fetal neurons has been limited by scarcity of appropriate tissue sources, logistic problems, legal and ethical constraints, and poor survival of grafted neurons in the human host brain.
One method replaces neurons by using marrow stromal cells as stem cells for non-hematopoietic tissues. Marrow stromal cells can be isolated from other cells in marrrow by their tendency to adhere to tissue culture plastic. The cells have many of the characteristics of stem cells for tissues that can roughly be defined as mesenchymal, because they can be differentiated in culture into osteoblasts, chondrocytes, adipocytes, and even myoblasts. Therefore, marrow stromal cells present an intriguing model for examining the differentiation of stem cells. Also, they have several characteristics that make them potentially useful for cell and gene therapy. Prockop, D.J.
Science:
26: 71-74 (1997). This population of bone marrow cells (BMSC) have also been used to prepare dendritic cells, (K. Inaba, et al.,
J. Experimental Med
. 176: 1693-1702 (1992)) which, as the name implies, have a morphology which might be confused for neurons. Dendritic cells comprise a system of antigen-presenting cells involved in the initiation of T cell responses. The specific growth factor which stimulates production of dendritic cells has been reported to be granulocyte/macrophage colony-stimulating factor (GM-CSF). K. Inaba, et al.,
J. Experimental Med
. 176: 1693-1702 (1992).
The presence of stem cells for non-hematopoietic cells in bone marrow was first suggested by the observations of the German pathologist Cohnheim 130 years ago. J. Cohnheim,
Arch. Path. Anat. Physiol. Klin. Med
. 40: 1 (1867). Cohnheim studied wound repair by injecting an insoluble aniline dye into the veins of animals and then looking for the appearance of dye-containing cells in wounds he created at a distal site. He concluded that most, if not all, of the cells appearing in the wounds came from the bloodstream, and, by implication, from bone marrow. The stained cells included not only inflammatory cells but also cells that had a fibroblast-lik
Freeman Thomas
Janssen William
Sanberg Paul
Sanchez-Ramos Juan
Song Shijie
Kunz Gary
Luther Barbara J.
Sierra Patent Group Ltd.
Turner Sharon
University of South Florida
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