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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