Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2000-12-07
2002-12-24
Vollano, Jean F. (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S648000, C514S721000, C514S741000
Reexamination Certificate
active
06498191
ABSTRACT:
THE TECHNICAL FIELD
The present invention relates generally to mitochondria protecting agents for treating diseases in which mitochondrial dysfunction leads to tissue degeneration and, more specifically, to compounds, compositions and methods for treating such diseases.
BACKGROUND OF THE INVENTION
Mitochondria are the subcellular organelles that manufacture essential adenosine triphosphate (ATP) by oxidative phosphorylation. A number of degenerative diseases may be caused by or associated with either direct or indirect alterations in mitochondrial function. These include Alzheimer's Disease, diabetes mellitus, Parkinson's Disease, neuronal and cardiac ischemia, Huntington's disease and other related polyglutamine diseases (spinalbulbar muscular atrophy, Machado-Joseph disease (SCA-3), dentatorubro-pallidoluysian atrophy (DRPLA) and spinocerebellar ataxias 1, 2 and 6), dystonia, Leber's hereditary optic neuropathy, schizophrenia, and myodegenerative disorders such as “mitochondrial encephalopathy, lactic acidosis, and stroke” (MELAS), and “myoclonic epilepsy ragged red fiber syndrome” (MERRF).
Defective mitochondrial activity, including but not limited to failure at any step of the elaborate multi-complex mitochondrial assembly, known as the electron transport chain (ETC), may result in 1) decreases in ATP production, 2) increases in the generation of highly reactive free radicals (e.g., superoxide, peroxynitrite and hydroxyl radicals, and hydrogen peroxide), 3) disturbances in intracellular calcium homeostasis and/or 4) release of apoptosis inducing factors such as, e.g., cytochrome c. Because of these biochemical changes, mitochondrial dysfunction has the potential to cause widespread damage to cells and tissues For example, oxygen free radical induced lipid peroxidation is a well established pathogenetic mechanism in central nervous system (CNS) injury such as that found in a number of degenerative diseases, and in ischemia (i.e., stroke).
Mitochondrial dysfunction also is thought to be critical in the cascade of events leading to apoptosis in various cell types (Kroemer et al.,
FASEB J.
9:1277-1287, 1995). Altered mitochondrial physiology may be among the earliest events in apoptosis (Zamzami et al.,
J. Exp. Med.
182:367-377, 1995, Zamzami et al.,
J. Exp. Med.
181:1661-1672, 1995. In several cell types, including neurons, reduction in the mitochondrial membrane potential (&Dgr;&PSgr;m), a sign of mitochondrial dysfunction, precedes the nuclear DNA degradation that accompanies apoptosis. In cell-free systems, mitochondrial, but not nuclear, enriched fractions are capable of inducing nuclear apoptosis (Newmeyer et al.,
Cell
70:353-364, 1994). Perturbation of mitochondrial respiratory activity leading to altered cellular metabolic states may occur in mitochondria associated diseases and may further induce pathogenetic events via apoptotic mechanisms. For example, altered mitochondrial activity may lead to undesirable elevated levels of intracellular reactive oxygen species (ROS) and subsequent intracellular damage or cell death.
Stressed (e.g., stressors included free radicals, high intracellular calcium, loss of ATP, among others) mitochondria may release pre-formed soluble factors that can initiate apoptosis through an interaction with novel apoptosomes (Marchetti et al.,
Cancer Res.
56:2033-2038, 1996; Li et al.,
Cell
91:479-489, 1997). Release of preformed soluble factors by stressed mitochondria, like cytochrome c, may occur as a consequence of a number events. In some cases, release of apoptotic molecules (apoptogens) occurs when mitochondria undergo a sudden change in permeability to cytosolic solutes under 1.5 KDa. This process has been termed permeability “transition”. In other cases, the permeability may be more subtle and perhaps more localized to restricted regions of a mitochondrion. In still other cases, overt permeability transition may not occur but apoptogens can still be released as a consequence of mitochondrial abnormalities. Thus, changes in mitochondrial physiology may be important mediators of apoptosis. To the extent that apoptotic cell death is a prominent feature of degenerative diseases, mitochondrial dysfunction may be a critical factor in disease progression.
Diabetes mellitus is a common, degenerative disease affecting 5 to 10 percent of the population in developed countries. The propensity for developing diabetes mellitus is reportedly maternally inherited, suggesting a mitochondrial genetic involvement (Alcolado et al.,
Br. Med. J.
302:1178-1180, 1991; Reny,
International J. Epidem.
23:886-890, 1994). Diabetes is a heterogeneous disorder with a strong genetic component; monozygotic twins are highly concordant and there is a high incidence of the disease among first degree relatives of affected individuals.
At the cellular level, the degenerative phenotype that may be characteristic of late onset diabetes mellitus includes indicators of altered mitochondrial respiratory function, for example impaired insulin secretion and responsivity, decreased ATP synthesis and increased levels of reactive oxygen species. Studies have shown that diabetes mellitus may be preceded by or associated with certain related disorders. For example, it is estimated that forty million individuals in the U.S. suffer from late onset impaired glucose tolerance (IGT). IGT patients fail to respond to glucose with increased insulin secretion. A small percentage (5-10%) of IGT individuals progress to insulin deficient non-insulin dependent diabetes (NIDDM) each year. Some of these individuals further progress to insulin dependent diabetes mellitus (IDDM). These forms of diabetes mellitus, NIDDM and IDDM, are associated with decreased release of insulin by pancreatic beta cells and/or a decreased end-organ response to insulin. Other symptoms of diabetes mellitus and conditions that precede or are associated with diabetes mellitus include obesity, vascular pathologies, peripheral and sensory neuropathies, blindness and deafness.
Due to the strong genetic component of diabetes mellitus, the nuclear genome has been the main focus of the search for causative genetic mutations. However, despite intense effort, nuclear genes that segregate with diabetes mellitus are known only for rare mutations in the insulin gene, the insulin receptor gene, the adenosine deaminase gene and the glucokinase gene. Accordingly, mitochondrial defects, which may include but need not be limited to defects related to the discrete non-nuclear mitochondrial genome that resides in mitochondrial DNA, may contribute significantly to the pathogenesis of diabetes mellitus.
Parkinson's disease (PD) is a progressive, mitochondria associated neurodegenerative disorder characterized by the loss and/or atrophy of dopamine-containing neurons in the pars compacta of the substantia nigra of the brain. Like Alzheimer's Disease (AD), PD also afflicts the elderly. It is characterized by bradykinesia (slow movement), rigidity and a resting tremor. Although L-Dopa treatment reduces tremors in most patients for a while, ultimately the tremors become more and more uncontrollable, making it difficult or impossible for patients to even feed themselves or meet their own basic hygiene needs.
It has been shown that the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces parkinsonism in animals and man, at least in part through its effects on mitochondria. MPTP is converted to its active metabolite, MPP
+
, in dopamine neurons; it then becomes concentrated in the mitochondria. The MPP
+
then selectively inhibits the mitochondrial enzyme NADH:ubiquinone oxidoreductase (“Complex I”), leading to the increased production of free radicals, reduced production of adenosine triphosphate and, ultimately, the death of affected dopamine neurons.
Mitochondrial Complex I is composed of 40-50 subunits; most are encoded by the nuclear genome and seven by the mitochondrial genome. Since parkinsonism may be induced by exposure to mitochondrial toxins that affect Complex I acti
Davis Robert E.
Ghosh Soumitra S.
Miller Scott W.
Moos Walter H.
MitoKor
SEED Intellectual Property Law Group PLLC
Vollano Jean F.
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