1. Discuss the pathogenesis of fever and acute-phase response.

Show illustration

• Fever definition
o Elevation of body temperature to above normal (98.40F) or 370C orally or 99.80F or 37.60C rectally)
• Challenge to fever
o To establish the causative agent – distinguish viral from bacterial disease
o Identify the site of a localized infection

o Physiologic states • Common causes of fever • Mechanisms of a Protective

causing fever: o Minor illness Effect of Fever
 digestion  URTI o Enhanced neutrophil
 exercise  Viral exanthems migration
 ovulation  Gastroenteritis o Increased production of
 pregnancy  antibacterial substances by
 warm environment o Major illnesses neutrophils
 emotion  Bacterial meningitis o Increased production of
o Pathologic causes  UTI interferon
 Infection o Increased antiviral and
 Pneumonia
 Inflammation e.g. antitumor activity of
 Malaria
connective tissue interferon
disease o Increased T-cell proliferation
 Neoplasms o Decreased growth of
 Vaccines microorganisms in iron-poor
 Dehydration environment
Illustration:

• Pathogenesis of fever

Exogenous pyrogens:
Microbes, microbial toxins, other microbe products

Endotoxins ( bacterial toxin)

PML, Monocytes, Macrophages

Endogenous pyrogens: IL-1;IL-6;TNF-a & IFN –B and Y

Thermosensitive neurons (Anterior hypothalamus)

FEVER

Thermoregulatory responses:
 Redirection of blood to and from Cutaneous vascular
beds
 Increased or decreased sweating
 ECF volume regulation
 Behavioral changes

• Why Fever Occurs

Exogenous pyrogens: e.g.infectious agents, drugs

White blood cells

(macrophages, monocytes, neutrophils)

Cytokines e.g. IL-1, TNF

Hypothalamus in brain

Prostaglandins

FEVER
 Pathogenesis of fever

If the body temperature is above 37,2 C and is associated with

sweating, hyperventilation, and vasodilatation in the skin, we speak of
fever. At the beginning, gradual increase in body temperature is observed
together with muscle shivering, vasocontriction in the skin, and
piloerection. This situation is called chills. Increased body temperature is
achieved by lowered loss of heat. Vasoconstriction in the skin and
subcutaneous tissue is the cause of pale color and dryness, the affected
person has a feeling of coldness. At the same time the production of heat in the organism
increases. The muscle tonus increases, the spasms accur. Spasms may occur mainly in children.
When the vasodilatation starts in the skin, the feeling of warmth and sweating occurs.

Fever may be provoked by many stimuli. Most often, they are bacteria and their
endotoxins, viruses, yeasts, spirochets, protozoa, immune reactions, several hormones,
medications, and synthetic polynucleotides. These substances are commonly called exogenic
pyrogens. Cells stimulated by exogenic pyrogens form and produce cytokines called endogenic
pyrogens. Endogenic pyrogens centrally affect the thermosensitive neurons in the preoptic area
of the hypothalamus increase the production of heat and decrease in heat loss. The body
temperature increses until it reaches the set point. This information is transferred by temperature
of blood that flows around the hypothalamus. The decrease of temperature is controlled by
activation of mechanisms regulating increased outcome of heat to the surrounding area.
Increased outcome continues in favourable case until the new equilibrium is achieved.

The most important endogenic pyrogens are IL-1, IL-6 and cachectin also called the
tumour necrosis factor- (TNF- ). These are glycoproteins that also have other important
effects. They are produced especially by monocytes and macrophages but also by endothelial
cells and astrocytes. Also the interferons , and display the pyrogenic activity.

After administration an endotoxin in an experiment, the level of plasmatic TNF- increases and
fever occurs. Increased concentrations of IL-1 and TNF- are also found in sepsis. The
production of these cytokines is regulated by the positive feedback mechanism. Besides this,
macrophages activated by IFN- may increase the production of IL-1 and TNF- primary
induced by other stimuli. On the other hand, glucocorticoids and prostaglandins of group E may
display inhibitory effect on the production of IL-1 and TNF- . Released IL-1 and TNF- are
transported by blood. They affect the target cells in the close proximity or in distant sites. The
target cells have specific receptors for IL-1 and TNF- . In the hypothalamus, IL-1 and TNF-
trigger the synthesis of prostaglandis of group E from the arachidonic acid of cytoplasmic
membranes of target cells. Precise mechanism by which prostaglandin PGE reset the central
thermostat, is not known. Aspirin and the non-steroidal antiphlogistics display antipyretic
activity by inhibiting the cyclo-oxygenase, an enzyme responsible for the synthesis of PGE
(these antipyretics don't inhibit the production of TNF- or IL-1). Glucocorticoids work
antipyretically by inhibiting the production of IL-1 and TNF- , and by inhibiting the metabolic
processes of arachidonic acid.

In the process of fever, IL-1 and TNF- play the central role. Except introduced
activity in fever, they interfere with many mechanisms in an organism. Some of their effects
are executed with the participation of metabolites of arachidonic acid. IL-1 and TNF- affect
myelopoesis, release of neutrophils and enhancement of their functions. They cause
vasodilatation and the increase the adhesivity of cells, increase the production of PAF and
thrombomodulin by endothelial cells, proteolysis and glycogenolysis in muscles, mobilisation of
lipids from adipocytes, proteosynthesis and glycogenolysis in the liver, induce proliferation of
fibroblasts, activate osteoclasts and the release of collagenase from chondrocytes, induce slow
wave sleeping activity in the brain, the release of ACTH, beta endorfins, growth hormone and
vasopressin, the release of insulin, cortisol, and catecholamines. TNF- and partially also IL-1 in
longlasting operation may cause cachexia mainly by decreasing the appetite. It is so in chronic
infections, inflammatory processes, and in neoplastic processes.

Beside that, TNF and IL-1 significantly increase the immune response by activation of T-cells
and stimulation of IL-2 production. IL-1 enhances B-cells proliferation. It is interesting that these
processes have the temperature optimum at 39,5 . It follows that the fever can be supposed as
a positive factor. Fever and specific effects of IL-1 and TNF- form together highly integrated
processes that are involved in the response to infection and acute inflammation processes.

Interferons, and especially IFN- (formed by T lymphocytes and NK cells) may enhance this
reponse. Several parts of this complex response have protective and the others may have
malignant consequences. Septicemia, or septic shock is an overshot response of the organism. In
this complicated reaction of the organism, it is not easy to decide whether fever should be treated
by antipyretics or not. By antipyretics the symptoms of fever may be suppressed but it is
uncertain if it is reasonable to suppress also the positive efects of fever and everything that is
connected with it. This complex process (fever) mobilizes not only the immune system but also
those processes that improve the nutrition of cells and have protective importance on their
activity.

In the majority of diseases, fever is caused by pyrogens. There are situations, when fever may be
caused directly by changes in the center of thermoregulation without the participation of
exogenic and may be also endogenic pyrogens. This occurs in brain tumours, intracranial
bleeding, and thrombosis.

Acute Phase Response

Increasing levels of prostaglandin E2 in the brain induce an
area called the hypothalamus to turn up the body's thermostat a notch.
Suddenly, the same external temperature feels colder, and various
means are employed to restore the subjective impression of warmth.
These include involuntary processes such as shivering, which
generates heat by movement, and voluntary behavior such as putting
on more clothes, finding a warm radiator to sit next to, and so on.

Like pain and swelling, fever plays a vital part in defending the
body against infection. Many bacteria reproduce most effectively at
normal body temperature. So by raising body temperature the rate at which the bacteria can
divide is slowed down. Fever has the opposite effect on most immune cells, causing them to
divide more quickly. So fever both slows down the spread of the infection and accelerates the
counterattack by the immune system.

All injuries and infections, as stated above, cause a fever. This might only manifest itself
in a localised heat, and does not always produce an overall increase of the body temperature.

Mechanism of the Acute Phase Response

In response to acute damage or entrance of foreign material monocytes enlarge and

synthesise increased amounts of enzymes which help to break down the material. In doing so
they are transformed to more active phagocytes called macrophages. Monocytes are formed in
the bone marrow, enter the blood stream and have a longer life than neutrophils (T and B
lymphocytes, "white blood cells"), estimated at 12 to 24 hours. Monocytes respond to
chemotactic and immobilising factors (migration inhibitory factor) excreted by lymphocytes.
This allows them to "stick" at the debris site.

Macrophages have surface receptors for antibodies and are capable of synthesising
various proteins as messengers. An important function of the macrophage is the presentation of
debris material to B and T cells. Large molecules or particular substances, however, require
digestion by the macrophage before they can be recognised by the other cells of the immune
system. Bits of these materials will be displayed on the surface of the macrophage and via
contact stimulate both B and T cells into appropriate action.

Lymphocytes (including B and T cells) mainly produce immunoglobulins (antibodies)

and are also responsible for cellular immunity. Cellular immunity is involved in delayed
hypersensitivity (allergies and various overreactions of the body) and homograft rejection.
Lymphocytes can also damage foreign cells (bacteria, parasites, fungi, etc.). Human lymphocytes
are formed chiefly in the bone marrow. Normal T cells develop only in the presence of a normal
functioning thymus. Long lived lymphocytes are primarily T cells, that recirculate through the
spleen and the lymph nodes, thoracic duct and bone marrow, leaving and re-entering the
circulation repeatedly. There are subpopulations of T cells which serve to enhance (helper T) or
reduce (suppressor T) B-cell responses. It is not yet known precisely how the various surface
receptors on T and B cells influence cell function, but they are probably involved in antigen
recognition and cell-to-cell interactions with macrophages and other lymphocytes.

We see the various cells involved in the process under our powerful microscopes in still
pictures. We also can measure various substances at various points throughout the inflammation
process and we can identify certain specific sites on the cell surface. From this information we
piece together the story of cellular immunity. In fact, we tell a number of "separate" stories about
the immunological response. There is the story about how antibodies are first formed and then
used to illicit a rapid response when exposed to the same "intruder" again. There is the story of
how the immune system responds to a bacterial, or similar, invasion. There is the story of how
the immune system creates tolerance for the prevention of immunologically induced self-injury.
There is the story of autoimmunity, whereby antibodies are formed against the body's own tissue,
which will consequently be attacked. There is the story of anaphylaxis, an extreme overreaction
of the body defence mechanism. There is the story of the complement system, which consists of
at least 15 plasma proteins which interact sequentially, producing substances that mediate several
functions of inflammation. A lot of stories in which different substances and pathways are
described, but without any serious linking of the various stories or without any knowledge as to
why and how the body chooses to follow that particular pathway on that particular occasion.

Returning to the acute phase response, the story we are particularly interested in, we
know that there are many different cytokines (messengers) involved. One of the first cytokines to
be released by the macrophages on detecting signs of injury or infection is known as interleukin-
1ß (IL-1ß). It diffuses into the tissue surrounding the damaged cells, where it triggers a second
wave of cytokines which cause other types of immune cells such as neutrophils and monocytes
to migrate to the injured site. The IL-1ß released by the macrophages also enters the blood
stream, where it is carried to the brain, but is prevented from entering the brain directly by a
layer of cells known as the blood-brain barrier. It therefore adopts a more cunning route into the
central nervous system. First, the IL-1ß molecules attach themselves to specially designed
receptors on the surface of the cells in the blood-brain barrier. When these receptors are
activated, a chain reaction is initiated that eventually leads to the manufacturing of a molecule
known as prostaglandin E2, which, unlike IL-1ß, is capable of passing through the blood-brain
barrier. When it enters the brain, prostaglandin E2 activates the receptors on both neurons and
microglia (immune cells in the brain), which can then initiate the other components of the acute
phase response: fever, lethargy, apathy, loss of appetite, anxiety, and increased sensitivity to pain
in other areas of the body. But the story does not end there. Once inside the brain, prostaglandin
E2 encourages the microglia to manufacture IL-1ß. The net result is that, although IL-1ß cannot
cross the blood-brain barrier directly, a build-up of IL-1ß in the blood stream leads to a build-up
of IL-1ß in the brain and the cerebrospinal fluid. To complete the cycle, the IL-1ß leads to further
synthesis of prostaglandin E2 in the brain, which in turn augments the various components of
sickness behaviour.

To compensate for the decreased supply of new calories caused by the loss of appetite,
the body starts to unleash old calories that have been stored up for just such times of
emergencies. These calories are stored in fat deposits around the body, but before the fat can be
used as a source of energy it must be broken down into glucose. So another crucial component of
the acute phase response is the secretion of glucocorticoids, which trigger the process of
converting fat to glucose. The key glucocorticoid in humans is cortisol, which is released by the
adrenal glands in response to a cascade of chemical signals initiated in the brain by IL-1ß. First,
the IL-1ß stimulates the hypothalamus to secrete a chemical called corticotrophin releasing
hormone (CRH). The CRH travels to the pituitary gland, just below the brain, where it triggers
the release of another chemical called adrenocorticotrophic hormone (ACTH). Finally, the
ACTH reaches the adrenal glands, which secrete the cortisol. Because of their close
interconnections, the three anatomical structures involved in this chemical cascade are known
collectively as the hypothalamo-pituitary-adrenal axis.

Conclusion:
Fever appears to have evolved in vertebrate hosts as an adaptive mechanism for
controlling infection. This phenomenon is produced by certain exogenous (largely microbial)
stimuli that activated bone-marrow-derived phagocytes to release a fever-inducing hormone
(endogenous pyrogen). Endogenous pyrogen, in turn, circulates to the thermoregulatory center of
the brain (preoptic area of the anterior hypothalamus) where it causes an elevation in the "set-
point" for normal body temperature. Warm blooded animals produced fever by increasing heat
production (through shivering) or reducing heat loss (by peripheral vasoconstriction), whereas
cold blooded animals do so only by behavioral mechanisms (seeking a warmer environment).

Fever is a part of the acute phase response to infection and inflammation. We now
understand that fever is a complex physiological response that is aimed at facilitating survival of
the host. The fever is induced by endogenous inflammatory mediators, such as prostaglandins
and pyrogenic cytokines, that are released by immune cells activated by exogenous pyrogens.
Although the pathways (humoral and/or neuronal) responsible for transfer of the pyretic signals
from the blood to the brain are still under discussion, it is generally accepted that they act on the
level of the anterior hypothalamus to raise the thermoregulatory set-point. Results of studies of
the adaptive value of fever demonstrate an association between a rise in body temperature and a
decrease in mortality and morbidity during infection. These data along with data from
evolutionary studies provide a strong support for the concept that fever is a beneficial during
infection in endotherms and ectotherms, vertebrates as well as in invertebrates. There are also
evidence showing that fever may be used as a therapeutic tool, especially in cancer therapy.
Fever has evolved as a host defense mechanism which was preserved within the animal kingdom
through hundreds of millions of years of evolution.
 The Immune System
In relation to infection & inflammation to Fever

There are physical, chemical, and cellular defenses against invasion by viruses, bacteria, and
other agents of disease.

During the early stages of an infection, there is an inflammatory response

• Non-specific attack
• Phagocytes active ("eat" pathogen)

During later stages, leucocytes produce immune responses

• Antigen - a foreign substance which triggers an immune response

• Some WBC's produce antibodies in huge amounts
o Antibodies - substances which bind to specific antigens and tag them for
destruction
o Other WBC's (executioner cells) directly destroy body cells

Surface coverage - the first line of defense

• The body is protected from pathogens by the skin and mucous membranes
o Skin - dead cellular layer - dry, low pH
o Mucous membranes contain lysozymes (enzymes which break down bacteria)
o Other cells contain cilia which filter pathogens and particulates
• Breaks in the protective barrier
o Digestive openings
o Reproductive openings
o Respiratory openings
o Sensory Organs

Non-specific responses - the second line of defense

• Non-specific responses are generalized responses to pathogen infection - they do not

target a specific cell type
• The non-specific response consist of some WBC's and plasma proteins
• Phagocytes - cells which "eat" foreign material to destroy them
o Phagocytes are formed from stem cells in bone marrow (stem cells are
undifferentiated WBC's)
 Neutrophil - phagocytize bacteria
 Eosinophils - secrete enzymes to kill parasitic worms among other
pathogins
• Macrophage - "big eaters" phagocytize just about anything
 Macrophage destroying bacterial cells

• Non-phagocytic leucocytes -
o Basophil - contain granules of toxic chemicals that can digest foreign
microorganisms. These are cells involved in an allergic response
o Mast Cells - similar to basophils, mast cells contain a variety of inflammatory
chemicals including histamine and seratonin. Cause blood vessels near wound to
constrict.
• Complement proteins - plasma proteins which have a role in nonspecific and specific
defenses

o Form a cascade effect - if only a few are activated, they will trigger others to
become active in great numbers
 Some punch holes in bacterial walls (forms holes where cellular
components leak out)
 Some promote inflammation
 Concentration gradients attract phagocytes to irritated or damaged
tissue
  Encourage phagocytosis in phagocytes (promotes "eating")
 Some bind to the surface of invading organisms
• Chemokines - create a chemical gradient to attract neutrophils and other leucocytes to
the wound site
• Inflammation

o Causes localized redness, swelling, heat, and pain

o Changes in capillary wall structure allow interstitial fluid and WBC's to leak out
in tissue
o Promotes macrophage (phagocytic WBC's) activity
o Macrophages secrete Interleukins (communication proteins among WBC's)
 Interleukin-1: increases body temperature (i.e. causes a fever)
 This enhances the WBC's ability to protect the body
 Causes drowsiness - reduces the body's energy usage and stress

The Immune System (Specific Responses) - the third line of defense

• Called into action when nonspecific methods are not enough and infection becomes
widespread

Types of cells involved in the immune system:

• Macrophages - engulf foreign objects

o Inform T lymphocytes at a specific antigen is present
• Helper T cells - produce and secrete chemicals which promote large numbers of effector
and memory cells
• Cytotoxic T cells - T lymphocytes that eliminate infected body cells and tumor cells
• B cells - produce antibodies (secrete them in the blood or position them on their cell
surfaces)

Each type of virus, bacteria, or other foreign body has molecular markers which make it unique

• Host lymphocytes (i.e. those in your body) can recognize self proteins (i.e. those which
are not foreign)
 • When a nonself (foreign) body is detected, mitotic activity in B and T lymphocytes is
stimulated
o While mitosis is occurring, the daughter populations become subdivided
 Effector cells - when fully differentiated, they will seek and destroy
foreign
 Memory cells - become dormant, but can be triggered to rapid mitosis if
pathogen encountered again

Thus, immunological specificity and memory involve three events:

(1) Recognition of a specific invader

(2) Repeated cell divisions that form huge lymphocyte populations

(3) Differentiation into subpopulations of effector and memory cells

• Antigen - a nonself marker that triggers the formation of lymphocyte armies

• Antibodies - molecules which bind to antigens and are recognized by lymphocytes

Antigen-presenting cell - a macrophage which digests a foreign cell, but leaves the antigens
intact. It then binds these antigens to MHC molecules on its cell membrane. The antigen-MHC
complexes are noticed by certain lymphocytes (recognition) which promotes cell division
(repeated cell divisions)

Molecular cues that stimulate lypmphocytes to create an immune response

T cells (Helper T cells and Cytotoxic T cells)

 • T cells arise from stem cells in the bone marrow - they then travel to the thymus where
the differentiate and mature. At maturity, they acquire receptors for self markers (MHC
molecules) and for antigen-specific receptors. They are then released into the blood as
"virgin" T cells.
• T cells ignore other cells with MHC molecules and they ignore free-floating antigens.
However, they will bind with a antigen-presenting macrophage (a macrophage possessing
a MHC-antigen complex). This binding promotes rapid cell division and differentiation
into effector and memory cells (all with receptors for the antigen)
• Effector helper T cells secrete interlukins (stimulate both T and B cells to divide and
differentiate)
• Effector cytotoxic T cells recognize infected cells with the MHC-antigen complex. They
then destroy the cell with perforans (enzymes which perforate the cell membrane,
allowing cytoplasm to leak out) and other toxins which attack organelles and DNA

Cell-mediated immune response

B cells and Antibodies

• B cells also arise from stem cells in the bone marrow. As they develop and mature, they
start synthesizing a single type of antibody
• Antibodies are proteins which recognize antigens
• The virgin B cell produces antibodies which move to the cell surface and stick out
• The B cell floats in the blood - when it encounters the specific antigen it becomes primed
for replication
• The B cell must receive an interleukin signal from a helper T cell which has already
become activated by a macrophage with a MHC-antigen complex. This promotes rapid
cell division.
• The B cell population then differentiates into effector and memory B cells
• The effector B cells then produce a staggering amount of free-floating antibodies
o When these free-floating antibodies encounter an antigen, they tag it for
destruction by phagocytes and complementary proteins
o These types of responses are only good for extracellular toxins and pathogens -
they cannot detect pathogens or toxins located inside of a cell
 Antibody-mediated immune response

Where do all of these interactions take place? - In the lymph nodes.

2. Explain the role of genetic engineering and gene therapy in the treatment of neurological
disorder.

Genetic engineering is the process of inserting new genetic information into natural cells
for the purpose to modify a specific organism by altering or enhancing genes. Since the 1970’s,
scientists have genetically engineered animals to repair genetic defects and enhance their
resistance to disease. Today, scientists genetically engineer animals to enhance their production
of useful substances that provide nutrition or treatment medication for humans. For example, a
sheep named Tracy was genetically enhanced to produce large quantities of human protein in her
milk. Similar to Tracy, cows are also being enhanced to produce extra proteins in their milk to
improve the nutritional value. A Hen named Brittany was also one of the first animals to be
genetically engineered. She was modified to produce eggs with high levels of protein, which are
useful to create anti-cancer drugs. Also, plants are genetically engineered for similar reasons. In
particular, they are enhanced to increase crop yields, crop quality (redness of a tomato, prolong
freshness), tolerate environmental extremes (cold, dry weather) and have greater resistance to
disease and pests.
As science around genetic engineering develops, humans may one-day be able to design
their children. Today, scientists hold the science to enhance the intelligence of animals, which
brings anticipation for future procedures on humans. Joe Tsien, a Princeton University
Neurobiologist, genetically engineered a single gene called NR2B into mice to control a brain
chemical called NMDA (N-methyl-D-aspartic acid) that plays a role in learning and memory.
Tsien’s results showed that after the gene was inserted into the mice, they produced more
NMDA. To prove that these mice attained enhanced intelligence, Tsien and his colleagues tested
the abilities of these mice compared to unmodified mice. These mice were put to tasks such as
recognizing objects in their environment and solving problems such as how to get out of water
and or off a high shelf. As a result, the genetically modified mice outperformed the unmodified
mice Tsien concludes that these findings suggest that enhancing the intelligence of humans may
be possible. He explains that the gene in humans that corresponds with memory and learning has
been found and how it performs in the brain is currently being studied.

Gene therapy is a medical procedure that may hold the cure for many of the diseases and
disorders of humankind. Gene therapy, a rapidly growing field of medicine, is the insertion of
genes into a person’s cells and tissues to treat an inherited disease. It is much like a transplant.
However, although transplanting a human heart or liver is complex, transferring genes involves
thousands of small molecules that cannot be seen with even the most powerful of microscopes.
Gene therapy aims to supplant a defective mutant gene with a gene that works. The technology is
still in its infancy but has been used with some success although many questions still surround
the procedure. To understand gene therapy, it is first necessary to understand heredity.
 Neurological conditions were once thought to be off-limits to gene therapy approaches
because of the blood–brain barrier. However, genetic research activity in this area is progressing.
Scientists are investigating the possibility of gene therapy to treat Alzheimer’s disease, epilepsy,
Parkinson’s disease, and other neurological diseases.

 ALZHEIMER’S DISEASE (AD)

Gene Therapy and AD
In 2006 researchers at the Salk Institute and the University of California, San Diego, have
used gene therapy to reduce memory loss in mouse models of AD by reducing the amount of an
important enzyme ß-secretase, or BACE1. According to Oded Singer, one of the authors of the
study, mice with AD overcame deficits after progressing to a severe level of the disease. This
finding is important because humans are usually not diagnosed until the disease has progressed
into recognizable stages. However, amyloid plaques can precede the onset of dementia by many
years. Enzymes cut the APP and release toxic fragments that stick together to form clumps. One
of the enzymes that damage APP is ß-secretase or BACE1.

Gene theraphy for alzheimer

They located the forebrain, where memory cells are held, and injected it
with 40 billion viruses through holes drilled on either side of the upper skull.
• The vector viruses went into the memory cells and released DNA into the
nucleus.
• The DNA produced NGF.
• NGF (nerve growth factor) was then released to the rest of the brain to maintain cells important
to memory.

 EPILEPSY
On 8 November 2006, researchers at the Children’s Hospital of Philadelphia announced
that they had inhibited the onset of epilepsy after a brain insult in animals. A brain insult is an
initial episode of epilepsy or an injury such as a severe head trauma; the patient often develops
epilepsy after such insults.
Using gene therapy to modify signaling pathways in the brain, neurology researchers,
Amy R. Brooks-Kayal and her colleagues significantly reduced the development of seizures in
rats. Seizures are caused by the rapid firing of brain cells and are thought to be caused by an
imbalance between the neurotransmitters and the glutamate system, which stimulates neurons to
fire, and the neurotransmitter gamma-aminobutyric acid (GABA), which inhibits that brain
activity. Working in a portion of the brain called the dentate gyrus, the scientists focused on type
A receptors for GABA. GABA(A) receptors are made up of five subunits of proteins that play an
important part in brain development and controlling brain activity. Rats with epilepsy had lower
levels of the alpha1 subunits of these receptors and higher levels of alpha4 subunits. The
researchers used gene therapy to alter the expression of alpha1 subunits and then injected an AD
virus carrying the gene that alters the expression of the protein in the brain. Later they injected
pilocarpine, a drug that causes status epilepticus (SE), a convulsive seizure. They found that rats
that received gene therapy had elevated levels of A1 proteins and either failed to develop
seizures or took three times as long to express spontaneous seizure compared to rats that did not
receive the gene.
According to Brooks-Kayal, this trial shows that there is a window for intervening after a
brain insult; it provides proof of the concept that altering signaling pathways in nerve cells after
such an insult could provide a scientific basis for prevention of epilepsy.

 PARKINSON’S DISEASE (PD)

In 1817 James Parkinson first described a neurological disorder in which patients have
shaking tremors in the hands, muscular stiffness, difficulty in balancing and walking, and
progressive physical and mental deterioration. The face takes on a frozen, mask-like expression
that may become fixed. PD is caused by the death of brain cells that produce a vital chemical
known as dopamine. A specific area of the midbrain, called the substantia nigra, that controls
motor coordination is affected. Treatment at present consists of giving a precursor of dopamine,
L-Dopa, which can diffuse into the brain. However, over a span of years the medicine becomes
less effective. PD may be a good target for gene therapy for the following reasons:
• Neurological damage is restricted to one area of the brain; this contrasts
with AD, in which the entire thinking part of the brain is affected and then
the damage spreads to other areas.
• A specific type of cell, the dopamine-producing neuron, is needed to
relieve the symptoms of PD.

Researchers experimenting with gene therapy in one PD treatment found longlasting

production of L-Dopa. Using adeno-associated viruses (AAV), researchers delivered two human
genes to the specific area of the brain: production was stable for 1 year and there were no
observable toxic effects after the treatment. Genetic research on PD is difficult and inconclusive.
Tracing of families with incidents of PD has to concentrate on geographical regions where a
condition might have appeared spontaneously in a single individual. The difficulty in this work is
that familial cases do not differ from sporadic cases.
Presenting at the Fourteenth Annual Congress of the European Society of Gene Therapy
in Athens, Greece, November, 2006, the UK firm Oxford BioMedica released preclinical efficacy
data on a gene-based product showing that ProSavin outperformed the standard L-Dopa
treatment for PD. Long-term therapeutic benefits showed benefits for at least 15 months without
loss of effects. Also, ProSavin does not induce the disabling dyskinesias, or movement disorders,
associated with L-Dopa. ProSavin is administered locally to the striatum area of the brain and
delivers genes for three enzymes that are required for the synthesis of dopamine. Oxford
BioMedica plans to start European phase I and phase II trials in 2007 in patients with late-stage
PD, and proposes a clinical plan to follow in a phase III trial, which could begin in 2009. A
different perspective on PD was published in the November 2006 issue of the British journal
Lancet Neurology. H. C. Fung and colleagues announced that there does not appear to be a gene
that strongly influences the risk of PD in most patients, although genes of small influence may
still be discovered.

Conclusion:

Advances in molecular biology have triggered an

unprecedented expansion of knowledge about human
genetics. The rise of new genetic technologies, and their
implied power, has engendered concerns among religious,
scientific, and civic leaders that these new technologies may
be growing more rapidly than our ability to prudently control
and productively use them. The ability to insert human genes
into human patients to treat specific genetic diseases–human
gene therapy and genetic engineering “engineering” of
humans– has been one of the concerns noted by those
observing the evolution of genetic technologies.
Human gene therapy will first be considered in a clinical situation where it might be
possible to treat with a human gene an individual patient suffering from a genetic disease. Gene
therapy would be attempted only when there is no other therapeutic alternative, or when the
alternatives are judged to be of greater risk or less potential benefit. Application of gene therapy
for a human genetic disease should require evidence that it is safe, might prove beneficial, is
technically possible, and is ethically acceptable. Judgments should be made in a procedurally
sound and objective regulatory framework.
Genetic engineering and gene therapy plays a role in the treatment of neurological
disorders. Making some adjustment or articulation in the genes of a human being can make a big
difference in health and well being of a person. Gene therapy could even enhance memory of an
Alzheimer’s patient, prevent & control seizure (Epilepsy), relieve symptoms of Parkinson
disease and even prevent further damage of the brain. Studies also show that genetic engineering
could enhance intelligence of a person based on the experiment done to a rat. Our technology
has gone so far. We have benefited a lot in our technology but it doesn’t stop here because it is
continually being developed to help uplift our lives. Hope we could use the new discoveries in a
good way so that there will always be a positive outcome. We should not abuse it instead we
must use it for the improvement of our life and better health.