Neurodegenerative Diseases

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About neurodegeneration

Neurons unlike most of the cells in the body have limited regenerative capacity. Thus, progressive damage or loss of neurons, neurodegeneration, has severe consequences on the mental and physical health of an individual. Neurodegeneration is a common feature for many neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Multiple Sclerosis and Amyotrophic lateral sclerosis. Neurodegeneration also occurs in response to stroke, heart attack, and head and spinal cord trauma. Typically these diseases affect elderly, progress slowly, and finally lead to disability and premature death.

Despite extensive research and huge R&D investments, there is still a large, unmet need for effective treatments that would manage the causes and halt the progression of neurodegenerative diseases. Current therapeutic interventions treat solely the symptoms. Great advances have been made during the 1990s in understanding the pathophysiological mechanisms leading to neurodegeneration. Although the etiology and background of these diseases are heterogeneous, the underlying mechanisms of damage to neurons are similar enabling development of drugs that target many disorders. E.g. neuroprotectants aim at preserving the function of the CNS by limiting the injury of neurons. Medeia Therapeutics develops small molecules and bone marrow stem cell-based therapies that significantly inhibit neurodegeneration, modify the pathogenesis of neurodegenerative diseases and lead to preserved cognitive and motor functions.

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Alzheimer’s disease (AD)

Alzheimer’s disease is the major form of dementia and the 4th leading cause of death. Approximately 20-30 million people worldwide suffer from AD and this number is predicted to quadruple by 2050 with increased life expectancy. The average age of onset is 75 years in the most common, sporadic form of AD. The incidence increases with advanced age being ∼10% in population over the age of 65, and ∼50% in 85-year-olds or elder.

The disease begins as mere forgetfulness and advances into more severe symptoms, such as poor judgement, confusion about time and place, personality change, irritability, and difficulty with performing daily tasks. Diagnosis is confirmed histologically by the presence of extracellular amyloid beta (Aβ) containing plaques and intraneuronal neurofibrillary tangles. The development of better diagnostic tools enabling earlier diagnosis of AD is under intensive research. Aβ, the 40 to 42-amino acid long peptide derived from the amyloid precursor protein (APP), plays a central etiological role in the disease. The histopathological features observed in AD are strikingly similar, although the disease is etiologically heterogeneous.

A rare form of AD is caused by autosomal dominant mutations in APP or presenilin genes that lead to elevation of highly fibrillogenic form of Aβ and early disease onset (30-40 years).  Also triplication of APP gene-containing chromosome 21 (Down’s syndrome) results in AD. The e4 allele of apolipoprotein E (apoE4) is the main known risk factor for the late-onset, sporadic form of AD.

There is no cure for AD. The current medications fall into two categories; acetylcholinesterase inhibitors and NMDA receptor antagonists, which offer only a transient relieve of the symptoms.

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Parkinson’s disease (PD)

Four million people worldwide have Parkinson’s disease. The average age of onset is 60 years. The incidence of PD is at 1% in people at the age of 65 and 2% in the population over the age of 80.
PD is a progressive neurological disorder marked by tremors, muscle rigidity, and balance and coordination problems. The degeneration of substantia nigra neurons that produce dopamine underlies these symptoms.


The degeneration of neurons is also associated with protein deposits called Lewy bodies. Mutations in the genes encoding two proteins, parkin and alpha-synuclein, are linked to separate, rare forms of inherited Parkinson’s disease, and are found in Lewy bodies that build up in the brains of all PD patients. Several studies have shown that PD patients have a loss of 80% of the neurons in the substantia nigra, but the ultimate reason for the degeneration of neurons is unknown.

At the moment, there is no way to prevent, stop or cure PD. Generally patients with PD are treated with drugs which either increase dopamine concentrations or reduce acetylcholine concentrations in the brain, but these drugs lose their effect with time, and have no impact on the disease progression.

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Amyotrophic lateral sclerosis (ALS)

The estimated incidence for ALS ranges from 0.4-1.8 per 100,000 people per year worldwide. Approximately 120, 000 new cases are diagnosed each year. The average age of onset is in the mid-50s, but ALS can occur at any time after the teen years.



ALS, sometimes called Lou Gehrig's disease, is a rapidly progressing, invariably fatal neurological disease that attacks the neurons responsible for controlling voluntary muscles. ALS causes weakness and eventually all muscles under voluntary control are affected. When muscles in the diaphragm and chest wall fail, patients lose the ability to breathe without ventilatory support. Most people with ALS die from respiratory failure, usually within 3 to 5 years from the onset of ALS symptoms.

The disease belongs to a group of disorders known as motor neuron diseases, which are characterized by the gradual degeneration and death of motor neurons. Motor neurons are nerve cells located in the brain, brainstem, and spinal cord that serve as controlling units and vital communication links between the nervous system and the voluntary muscles of the body.

The cause of ALS is not known, but mutations in the gene that produces the SOD1 enzyme are associated with some cases of familial ALS. This enzyme is a powerful antioxidant that protects the body from damage caused by free radicals. If not neutralized, free radicals can accumulate and cause random damage to the DNA and proteins within cells. 
No cure has yet been found for ALS.

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Spinal cord injury (SCI)

Approximately 250,000 – 400,000 individuals in the United States have spinal cord injury. Every year, approximately 34,000 new SCI cases occur in areas of major pharmaceutical market. Most of these people are injured in car and sports accidents, falls, and industrial mishaps. It is estimated that 60 % of these individuals are 30 years old or younger, and the majority are men.



The effects of SCI depend on the type and level of the injury. SCI can be divided into two types of injury - complete and incomplete. In complete injury there is no function below the level of the injury; no sensation and no voluntary movement. Both sides of the body are equally affected. In incomplete injury there is some functioning below the primary level of the injury.



SCI results in a rapid and significant necrosis of neuronal tissue at the site of injury. In the ensuing hours and days, secondary injury exacerbates the primary damage, resulting in significant neurologic dysfunction. It is believed that alterations in excitatory amino acids, increased reactive oxygen species and the disruption of intracellular Ca2+ homeostasis are the major factors contributing to the resulting neuropathology.

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Stroke

Stroke is the 3rd leading cause of death after cancer and heart disease and the leading cause of disability in the United States. There are approximately 700,000 new strokes in the US each year. Depending on the area of the brain that is damaged, a stroke can cause coma, paralysis, speech problems and dementia.



Cerebrovascular accident (CVA) is a clinical definition used to describe symptoms of an acute neurological disorder caused by disturbance of the cerebral blood supply. Intracerebral and subarachnoid hemorrhages account for approximately 20% of CVAs and 80% are of ischemic type. Stroke defines all conditions in which the duration of the CVA symptoms exceeds 24 h.

The causes of ischemic stroke include large artery atherosclerosis, small vessel occlusion, embolisms, and thrombosis. Focal (regional) ischemia is clinically more common than global (forebrain) ischemia. A focal insult usually occurs after thrombosis or embolus in the middle cerebral artery, whereas global ischemia results from transient cardiac arrest.

The brain requires glucose and oxygen to maintain neuronal metabolism and function. Hypoxia refers to inadequate delivery of oxygen to the brain, and ischemia results from insufficient cerebral blood flow. The consequences of cerebral ischemia depend on the degree and duration of reduced cerebral blood flow. Neurons can tolerate ischemia for 30-60 minutes, but perfusion must be re-established before 3-6 hours of ischemia have elapsed.



Injury from ischemic stroke is the result of complex series of metabolic processes that include increases in intracellular Ca2+, Na+ and Cl-, mitochondrial damage and production of free radicals, as well as formation of inflammatory mediators.

The treatment of stroke includes preventive therapies which reduce the likelihood of the disease. No efficient medical therapy is available beyond thrombolytic drugs such as t-PA that needs to be administered within a few hours after stroke.

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