parknison's disease and treatment
TRANSCRIPT
Parkinson’s Disease Treatment
Presented to : Dr.M.IsmailPresented by: Shumailah
NayabRoll # AP402818
INTRODUCTION TO PARKINSON’S DISEASE:
Parkinson’s disease is a progressive neurodegenerative disorder
Main histo-pathological feature is the loss of dopaminergic neurons in the pars compacta of the substantia nigra with secondary striatal dopaminergic insufficiency.
Although Parkinson's disease can't be cured, medications may markedly improve symptoms.
In occasional cases, doctor may suggest surgery to regulate certain regions of brain and improve symptom
Cardinal features:1. Bradykinesia (slowness and poverty of movement),2. Muscular rigidity, 3. Resting tremor (which usually abates during voluntary
movement), 4. Impairment of postural balance leading to disturbances
of gait and falling5. Loss of automatic movements6. Speech changes7. Writing changesCognitive and psychiatric dysfunctions like dementia and
depression also accompanies the clinical symptoms
CAUSES OF PARKINSON'S DISEASE?
•Progressive loss of brain cells (neurons) in a part of the brain substantia nigra, which produces the chemical dopamine.The neuron synaptically as well as dendritically releases dopamine are known as DA neurons They are positioned within three cell groups: ventral tegmental area (VTA),substantia nigra (SNc),retrorubral area •As the cells die, less dopamine is produced and transported to the striatum, the area of the brain that co-ordinates movement. •Symptoms develop as neurons die off and dopamine levels drop.
•Genetic factors: Gene mutations can cause Parkinson’s. Some of these mutations involve genes that play a role in dopamine cell functions e.g. alpha-synuclein, Parkin, PINK1, DJ-1 etc.•Environmental triggers: Exposure to certain toxins or environmental factors may increase the risk of later Parkinson's disease•NEURON LOSS: even mildly affected PD patients have lost about 60% of their DA neurons and it is this loss, in addition to possible dysfunction of the remaining neurons, that accounts for the approximately 80% loss of DA in the corpus striatum.
LEWY BODIES- major antigenic feature of Lewy
bodies is the expression of cellular proteins
involved in protein degradation. Presence of these
antigens has been hypothesized to represent efforts
on the part of the cell to degrade the abnormal
protein aggregate.
Presence of Alpha-synuclein within Lewy
bodies: A protein called alpha-synuclein α-
synuclein is found in all Lewy bodies in a clumped
form that cells can't break down. This is currently
an important focus among Parkinson's disease
researchers.
ETIOLOGIC FACTORS(risk Factors)
Age: Young adults rarely experience, and the risk increases
with age. People usually develop the disease around age 60 or
older
Heredity: Having a close relative with Parkinson's disease increases
the chances that you'll develop the disease.
Sex: Men are more likely to develop Parkinson's disease than are
women.
Exposure to toxins: Ongoing exposure to herbicides and pesticides
may put you at a slightly increased risk of Parkinson's disease.
• Exposure to MPTP (1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine) is a neurotoxin precursor
• heavy metal and hydrocarbon exposure
Complications
Thinking difficulties
Depression and emotional changes
Swallowing problems: accumulation of saliva in mouth due to
slowed swallowing, leading to drooling.
Sleep problems and sleep disorders: waking up frequently
throughout the night
Bladder problems: unable to control urine
Constipation
Blood pressure changes
Smell dysfunction
Fatigue
Pain: specific areas of body or throughout the body
Gene therapies for
Parkinson’s disease
What Are Genes?
• Genes are carried on chromosomes and are the basic physical and functional units of heredity .
• Genes are specific sequences of bases that encode instructions on how to make proteins.
• When genes are altered so that the encoded proteins are unable to carry out their normal functions, genetic disorders result.
Gene therapy is a new approach to treating medical conditions, which can be described as the use of genes as drugs.Gene therapy can also be used to treat disorders where the genetic cause is not known, or may not be caused exclusively by genetic defects, such as Parkinson’s. The carrier particle or molecule used to deliver genes are called as vectors.
DEFINATION: Gene therapy is the process of inserting genes into cell to treat diseases, where newly introduced genes will encode proteins and correct the deficiencies.
What Is Gene Therapy?
What Is Gene Therapy?
•A "normal" gene is inserted into the genome to replace an "abnormal," disease-causing gene. •A carrier molecule called a vector must be used to deliver the therapeutic gene to the patient's target cells. •The most common vector is a virus that has been genetically altered to carry normal human DNA. •Viruses have evolved a way of encapsulating and delivering their genes to human cells in a pathogenic manner. •Scientists manipulate the virus genome to remove disease-causing genes and insert therapeutic ones. •Target cells are infected with the viral vector.
How Does Gene Therapy Work?
Genetic
modifications
can either increase or reduce the expression of
specific genes
or
restore the normal function of the
product of these genes
Approaches for gene therapy
SOMATIC CELL GENE THERAPY
• Somatic cells are modified e.g.
bone marrow cells, blood cells,
skin cells
• Will not be heritable and passed
on to later generations
• At present all researches are
carried out in somatic cells
GERM CELL GENE THERAPY
• Germ cells, are modified by the
introduction of functional genes
e.g. eggs and sperms
• heritable and passed on to later
generations
• For safety, ethical and technical
reasons, it is not being
attempted.
TYPES OF GENE THERAPY
In vivo gene therapy• Direct injection of genetic
material using appropriate vectors
• Less invasive• Technically simple• Vector introduced directly• Safety check not possible• Decreased control over
target cells
Ex.vivo gene therapy• Patient’s cells are modified
outside the body and transplanted back
• More invasive• Technically complex• No vector introduced
directly• Safety check possible• Close control possible
Vectors for gene delivery
The carrier particle or molecule used to deliver genes are called as vectors.
The ideal vector system would have the following characteristics:
an adequate carrying capacity;
to be undetectable by the immune system;
to be non-inflammatory;
to be safe to the patients with pre-existing lung inflammation to have an efficiency sufficient to correct the cystic fibrosis phenotype
to have long duration of expression and/or the ability to be safely re-administered.
Categories of delivery vehicle (vector)1.Non-viral vectors: comprise chemical and physical methods, such as gene gun or electroporation2.Viral vectors:Viral vectors are engineered from wild-type viruses by removing the genes essential to their replication from their genomevectors have been developed, differing by their Packaging capacity: Capacity to have genomeTropism: cells and tissues of a host which support growth of a particular virus or bacteria. Immunogenicity: ability to induce a humoral and/or cell mediated immune response.
Lentivectors• Enveloped, ssRNA viruses from
the Retroviridae family, useful for ex vivo gene therapy
• To target neurons, lentivectors are typically pseudo-typed by replacing the wild-type envelope with the envelope of the vesicular stomatitis virus G (VSV-G). The resulting vectors have a broad cell tropism including neuronal and glial cells
• risk for insertional mutagenesis present
AAV-Based Vectors• adeno-associated viruses, 4.7 kb genome in ssDNA,
nonenveloped, belongs to parvoviridae family• AAVs depend on the coinfection with a helper virus,
such as adenovirus or herpes virus, for efficient replication inside the host cells
• Nonpathogenic in humans, capsid proteins induce only mild immune reactions
• Vectors derived from wild-type AAVs by the deletion of all the viral sequences except the ITRs (inverted terminal repeats).
SYMPTOMATIC THERAPIES
of Parkinson’s disease
Enzyme Replacement StrategiesDopamine is synthesized in the brain and transported from the substantia nigra to the striatum from diet
• Tyrosine hydroxylase (TH) - rate–limiting enzyme converts L–tyrosine L–3, 4–dihydroxy–phenyla–lanine (L–dopa)• Guanosine triphosphate cyclohydrolase I (GCH)- synthesizes the
essential TH co–factor tetrahydrobiopterine (BH4)• aromatic L–amino acid decarboxy–lase (AADC): L–dopa dopaminebased on the transfer of genes encoding the enzymes required for dopamine synthesis into the striatal GABAergic neurons phase IAAV vector–mediated gene delivery of AADC to the bilateral putamen (a structure in forebrain) - mean improvement was 46% phase IItrials of AAV–AADC are currently in the planning stages A vector derived from the equine infectious anaemia virus (EIAV) lentivirus, a phase I/II trial involving the triple gene transfer of TH, GCH and AADC into the bilateral putamen has been initiated at the Henri Mondor Hospital in France- mean improvement was 34%
Ectopic L-DOPA Conversion:
Genetic enzyme replacement
therapy can be used to increase
the efficacy of pharmacological L-
DOPA therapy degeneration of the
nigral dopaminergic neurons leads
to a decrease in striatal AADC
activity, which is essential for L-
DOPA conversion into dopamine.
Neurotrophic Factors:
Neurotrophic factors are a family of proteins that are responsible for
the growth and survival of developing neurons and the
maintenance of mature neurons.GDNF: glial cell line-derived
neurotrophic factor
Gene transfer of neurturin• protection of the nigrostriatal pathways from
progressive degeneration by providing genes encoding
for neurotrophic factors
• phase I gene therapy trial that introduced the
neurturin gene into the bilateral putamen through AAV
vector was conducted at the UCSF with mean
improvement of 36%
Glutamic Acid Decarboxylase: In PD, depletion of dopamine (striatum) activity of the sub thalamic nucleus (STN),
Globus pallidus (GPi) and to the substantia nigra pars reticulata (SNr) thalamo–cortical projection and brainstem nucleus motor symptoms such as bradykinesia and rigidity glutamic acid decarboxylase , a rate–limiting enzyme
required for the synthesis of inhibitory transmitter –aminobutyric acid (GABA), into the STN is aimed at converting excitatory output to inhibitory output
AAV–GAD given into the unilateral STN contra, 12 months after the vector infusion, the mean improvement on motor score of UPDRS was 27% in the off state and 24% in the on–state.
increase
increaseexcitatory drive
inhibitory effect
Problems With Gene Therapy
•Short-lived nature of gene therapy: patients will have to undergo multiple rounds of gene therapy.
•Immune response: risk of stimulating the immune system in a way that reduces gene therapy effectiveness is always a potential risk.
•Problems with viral vectors: viruses, the carrier of choice, present potential problems to the patient, like toxicity, immune and inflammatory responses, and gene control and targeting.
•Multi-gene disorders: most common disorders, such as heart disease, high blood pressure, Alzheimer's disease, arthritis and diabetes, are caused by the combined effects of variations in many genes.
•Chance of inducing a tumor (insertional mutagenesis): If the DNA is integrated in the wrong place in the genome, for example in a tumor suppressor gene , it could induce a tumor.
As such, gene therapy involves a great risk. There are several regulatory agencies whose permission must be sought before undertaking any work related to gene therapy. Recombinant DNA Advisory Committee (RAC) is the supervisory body of the National Institute of Health (NIH), USA, that clears proposals on experiments involving gene therapy.
WARNNIG…
References: 1-Arenas, E. Towards stem cell replacement therapies for Parkinson's disease. Biochemical and Biophysical Research Communications, 2010; vol 396: pp 152-156.2-Chen, J.C. Parkinson's disease: Health-Related Quality of Life, Economic Cost, and Implications of Early Treatment American Journal of Managing Care, 2010; vol 16: pp S87-S93. 3-Fricker-Gates, R.A. and Gates, M.A. Stem cell-derived dopamine neurons for repair in Parkinson's disease. Regenerative Medicine, March 2010; vol 5(2): pp267-78.4-Hauser, R.A., Early Pharmacologic Treatment in Parkinson's Disease. American Journal of Managing Care, 2010; vol 16: pp S100-S107. 5-Pahwa, R. and Lyons, K.E. diagnosis of Parkinson's disease: recommendations from diagnostic clinical guidelines. American Journal of Managing Care, 2010; vol 16: pp S194-S99.6-Lim ST, Airavaara M, Harvey BK 2010. Viral vectors for neurotrophic factor delivery: A gene therapy approach for neurodegenerative diseases of the CNS. Pharmacol Res 61: 14–267-Naldini L, Blömer U, Gallay P, Ory D, Mulligan R, Gage FH, Verma IM, Trono D 1996b. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 272: 263–267
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