There are many diseases, which haunt human beings with severe morbidity and mortality in spite of advancement of medicine and therapeutics. The neurodegenerative diseases, which haunt the senior citizens with a crippling illness, are on epidemic scale as life expectancy is on the rise world wise due to improved medical care. Few diseases were controlled with the discovery of newer drugs and few are still uncontrollable. Alzheimer's disease, which cripples the elderly people with dementia makes them socially irrelevant, and increases the burden of the family and the government. For an Alzheimer's patient, "There is no such thing is called as a day, for them every day is an other day". These are the words from the former President of USA, Ronald Regan because he himself is a victim of Alzheimer's disease. Is there no treatment to cure Alzheimer's? The field of pharmaceutical Biotechnology called as Gene Therapy said an excellent reply for this question.
Alzheimer's disease affects the cells of the brain. It is named after Alois Alzheimer, a German psychiatrist. The dreaded, mind-sapping disease that now plagues more than 4 million there are treatments that, for some victims, can hold back its progress. Alzheimer's disease is one of several disorders that cause the gradual loss of brain cells. It is a reversible type of dementia. Alzheimer's disease begins slowly. At first, the only symptom may be mild forgetfulness. People with Alzheimer's disease may have trouble remembering recent events, activities, or the names of familiar people or things. Simple math problems may become hard to solve. Such difficulties may be a bother, but usually they are not serious enough to cause alarm
Gene therapy is a technique for correcting defective genes for disease development. Now the field of biotechnology started focusing disease on its genetic level and was very much stressed towards a particular gene that is responsible for the disease development. Gene therapy is a technique for introducing the genetic material of a gene in a patient that lacks that gene because of a mutation.
Progression of Alzheimer's disease is given in an order fallows
X The first sign is in the Entorhinal cortex (near Hippocampus)
X The first sign involves the
1. Formation of Neuro fibrillary tangles
2. Formation of Neuritic Plaques.
X The Hippocampus (memory store) starts degenerating - this leads to breakdown in short term memory (recent memory)
X Because of this breakdown of memory, there is deterioration in routine task performance.
The patient shows disturbing behavioral disturbances like agitation, screaming,
Approaches of gene therapy comprises of following
1. A normal gene may be inserted into a nonspecific location within the genome to replace a nonfunctional gene.
2. This approach is most common. An abnormal gene could be swapped for a normal gene through homologous recombination.
3. The abnormal gene could be repaired through selective reverse mutation, which returns the gene to its normal function.
4 wandering.
5. There is a total wipe out of memory/recognition of others, no sense of self, no orientation of time and space in the last stages.
6 In the terminal stages, patients are totally dependent on family members.
7 The patients live for a long time, finally dying of some co-existing medical condition.
Various changes in the brain during Alzheimer's disease
X It can be diagnosed with 100 % certainty only on autopsy of brain
X Neurofibillary tangles
X Neuritic plaques
X Loss of brain cells and mass (only 1/3 rd of the normal weight)
X Change in blood flow and glucose utilization
Various causes of Alzheimer's disease
I) Neurotransmitters
X Acetylcholine (Ach) is responsible for learning and memory
X Ach is found abundantly in Hippocampus (memory store) and cerebral cortex
X It was thought at that time that Alzheimer's disease might disrupt the synthesis of Ach
X Alzheimer's disease might triggers the over- production of the enzyme that destroys Ach - Acetyl cholinesterase enzyme
X Apart from Ach, other
neurotransmitters implicated are serotonin, noradrenaline, and dopamine.
X Noradrenaline, dopamine deficits are responsible for sensory disturbances, aggressive behavior.
II) Cholinergic hypothesis
X Degeneration of Cholinergic neurons of Hippocampus and cerebral cortex in Alzheimer's disease leads to deficiency in Ach, which is responsible for loss of cognition, behavioral changes, mood disturbances.
III) Amyloid precursor protein (APP)
APP - normal protein produced by healthy neurons Responsible for growth and maintenance of neurons
Enzymes like a, b, g secretases cut APP to form A-beta protein ( which is insoluble , shorter and sticker )
A-beta protein (insoluble, sticker)
A-beta folds
Fibrils (insoluble)
Cluster and expand
PLAQUES
IV) Plaques
X Displaces or kills brain cells
X Damages cell's interiors
X Triggers an inflammatory response
X To fight this inflammatory response, brain generates toxic free radicals
V) Neurofibrillary tangles
X Neurons branch off at the ends forming neuritis.
X Neuritis made up of skeletal structures called Microtubules.
X Microtubule gives shape to neuron, transport nutrients, chemical messengers.
X Microtubules are glued together by Tau Proteins
X In healthy brain, Tau is firmly glued to the microtubules.
X In Alzheimer's disease, Tau proteins are destroyed by enzymes, leading to formation of Neurofibillary tangles.
X Without Tau proteins, neuronal cells shrinks, disintegrates and die.
VII) Genes:
X Evidence has boiled down to chromosomes 14, 19, 21 APOLIPO for Alzheimer's disease Protein E4 (Apo E4) gene
X Apo E4 leads to the insolubility of A- beta protein, forming Plaques.
Role of gene therapy
But actually gene therapy works in the following ways
1. A "normal" gene is inserted into the genome to replace an "abnormal," disease-causing gene.
2. A carrier molecule called a vector must be used to deliver the therapeutic gene to the patient's target cells.
3. The most common vector is a virus that has been genetically altered to carry normal human DNA
4 The duration of Alzheimer's disease from diagnosis to death can be 20 years or more, but the average duration is 5-8 years.
For the first time, gene therapy has been used in a human for the treatment of a brain disease. Neurosurgeons at the University of California in San Diego (UCSD) injected 2.5 million genetically modified cells into a 60-year-old woman's brain through a small hole drilled in her skull. The procedure took 11 hours. Scientists began by harvesting skin cells from the woman. Then they inserted into these skin cells the gene that directs the production of a protein called nerve growth factor (NGF). NGF is a naturally occurring protein in normal brains. One of its jobs is to keep brain cells alive by promoting growth and survival (much like food helps us grow and thrive). NGF helps the cholinergic system function properly. This system includes nerve cells that produce the neurotransmitter acetylcholine, a chemical signal the brain needs to process information and to function normally. In the brain of an Alzheimer's patient, the cholinergic cells wither and stop making acetylcholine. Low acetylcholine levels can cause problems with memory, emotions, and language. The procedure carried out by insertion of the modified skin cells into the nucleus basalis, a group of cells about the size of your thumbnail at the base of the frontal lobe. This area contains many cholinergic nerve cells. The cells were injected only into the right side of the brain.
Available nerve growth factor (NGF)
The available NGF synthesis stimulators are as follows:
a. Idebenone and
b. Propentofylline
(The authors are with Pharmacy Group, Birla Institute of Technology and Science, Pilani)