Stem cell research in Parkinson's Disease

Possible Future Treatment for Parkinson’sPossible Future Treatment for Parkinson’s
disease?disease?
Ms Veena Shriram.
Lecturer,
Dept of Physiology,
B.J. Medical College, Pune -1

Parkinson’s Disease (PD)Parkinson’s Disease (PD)
 First description 1817First description 1817
Parkinson, James An Essay on the Shaking Palsy.Parkinson, James An Essay on the Shaking Palsy.
 Progressive neurodegenerative diseaseProgressive neurodegenerative disease
 Affects ages 40 onwards, mean age atAffects ages 40 onwards, mean age at
diagnosis 70.5diagnosis 70.5
 Complex disorder with motor, non-motor,Complex disorder with motor, non-motor,
neuropsychiatric featuresneuropsychiatric features

 When most people reach for a pen, their body acts in one smooth andWhen most people reach for a pen, their body acts in one smooth and
controlled movement. The instant a person thinks of grabbing the pen,controlled movement. The instant a person thinks of grabbing the pen,
a series of nerve cells fire in an orchestrated symphony from the braina series of nerve cells fire in an orchestrated symphony from the brain
to the muscles responsible for that action.to the muscles responsible for that action.
 For the movement to be precise and smooth, all the nerve cells in theFor the movement to be precise and smooth, all the nerve cells in the
“grabbing-the-pen network” must function properly, including cells“grabbing-the-pen network” must function properly, including cells
that tell unneeded muscles to stay still.that tell unneeded muscles to stay still.
 In Parkinson’s disease (P. D.) the brain cells responsible for keepingIn Parkinson’s disease (P. D.) the brain cells responsible for keeping
unneeded muscles from movingunneeded muscles from moving degeneratedegenerate andand diedie..
 That is in P. D. nerve cells that make the chemicalThat is in P. D. nerve cells that make the chemical dopaminedopamine die. Thisdie. This
results in progressively more dramatic and uncontrolled movements,results in progressively more dramatic and uncontrolled movements,
tremors, and spasms.tremors, and spasms.
 To date, there is no cure for P. D. because no one has figured out a wayTo date, there is no cure for P. D. because no one has figured out a way
to bring back the specialized nerve cells that have died.to bring back the specialized nerve cells that have died.

Parkinson’s Disease (PD)Parkinson’s Disease (PD)
Parkinson's disease is a disorder of the brain
characterized by shaking (tremor) and difficulty
with walking, movement, and coordination. The
disease is associated with damage to a part of
the brain that is involved with movement.

Causes of PDCauses of PD
Parkinson‘s disease is caused by progressive deterioration of
the nerve cells of the part of the brain that controls muscle
movement. Dopamine, which is one of the substances used by
cells to transmit impulses, is normally produced in this area.
Deterioration of this area of the brain reduces the amount of
dopamine available to the body.
Insufficient dopamine disturbs the balance between dopamine
and other transmitters, such as acetylcholine. Without
dopamine, the nerve cells cannot properly transmit messages,
and this results in the loss of muscle function.

communication network in
nervous system

Healthy balance of dopamine
and acetylcholine
Imbalance of dopamine and
acetylcholine in Parkinson's
disease.

Signs and symptoms of Parkinson's diseaseSigns and symptoms of Parkinson's disease
Characterized by: (Characterized by: (SSlow,low, SStiff,tiff, SShaky)haky)
 Rest tremor--3-6Hz pill-rolling.Rest tremor--3-6Hz pill-rolling.
 Slowed motion (bradykinesia).
 Rigidity of muscles
 Loss of automatic movements
 Impaired speech
 Difficulty swallowing
 Dementia
 Postural instabilityPostural instability

 2002 Researchers injected Parkinson’s rats with mouse2002 Researchers injected Parkinson’s rats with mouse
embryonic stem cells. The rats showed a modest benefit for justembryonic stem cells. The rats showed a modest benefit for just
over 50% of the rats, but one-fifth (20%) of the rats died of brainover 50% of the rats, but one-fifth (20%) of the rats died of brain
tumors caused by the embryonic stem cells.tumors caused by the embryonic stem cells.
Bjorklund LM et al.,Bjorklund LM et al., Embryonic stem cells develop into functionalEmbryonic stem cells develop into functional
dopaminergic neurons after transplantation in a Parkinson rat model.dopaminergic neurons after transplantation in a Parkinson rat model.
Proc. Natl. Acad. Sci. 99, 2344-2349, February 19, 2002.Proc. Natl. Acad. Sci. 99, 2344-2349, February 19, 2002.
 20032003 DopaminergicDopaminergic neurons made from mouse embryonic stemneurons made from mouse embryonic stem
cells were transplanted into Parkinson's mice and provided somecells were transplanted into Parkinson's mice and provided some
decrease in symptoms, but 20% of mice receiving the embryonicdecrease in symptoms, but 20% of mice receiving the embryonic
stem cells died due to teratoma formation.stem cells died due to teratoma formation.
F Nishimura et al.,F Nishimura et al., Potential use of embryonic stem cells for thePotential use of embryonic stem cells for the
treatment of mouse Parkinsonian models: improved behavior bytreatment of mouse Parkinsonian models: improved behavior by
transplantation of in vitro differentiated dopaminergic neurons fromtransplantation of in vitro differentiated dopaminergic neurons from
embryonic stem cells.embryonic stem cells. Stem Cells 21, 171-180; March 2003.Stem Cells 21, 171-180; March 2003.

 2004 An Israeli team turned human embryonic stem cells (hES)2004 An Israeli team turned human embryonic stem cells (hES)
into neural progenitors and transplanted these into rats. Someinto neural progenitors and transplanted these into rats. Some
cells made dopamine, but the cells stopped growing at 12cells made dopamine, but the cells stopped growing at 12
weeks. The rats exhibited a partial improvement in behavioralweeks. The rats exhibited a partial improvement in behavioral
tests, but it was too early to see if tumors formed.tests, but it was too early to see if tumors formed.
Ben-Hur T, et al.,Ben-Hur T, et al., Transplantation of human embryonic stem cell-Transplantation of human embryonic stem cell-
derived neural progenitors improves behavioral deficit in Parkinsonsderived neural progenitors improves behavioral deficit in Parkinsons
rats.rats. Stem Cells 22 (7): 1246-55, 2004.Stem Cells 22 (7): 1246-55, 2004.
 2005 A Japanese team turned monkey embryonic stem cells2005 A Japanese team turned monkey embryonic stem cells
into neural stem cells. They transplanted these into monkeysinto neural stem cells. They transplanted these into monkeys
with artificially induced Parkinsons’s, and some cells turnedwith artificially induced Parkinsons’s, and some cells turned
into dopamine producing cells. There was mild alleviation ofinto dopamine producing cells. There was mild alleviation of
symptoms.symptoms. Yasushi Takagi et al.,Yasushi Takagi et al., Dopaminergic neurons generatedDopaminergic neurons generated
from monkey embryonic stem cells function in a Parkinson primatefrom monkey embryonic stem cells function in a Parkinson primate
model.model.

• 2006 Scientists in Sweden and Japan found no improvement of
Parkinson’s rats treated with embryonic stem cells, and many
animals developed severe tumors.
Brederlau A, et al., Transplantation of human embryonic stem cell-derived
cells to a rat model of parkinson’s disease: effect of in vitro differentiation
on graft survival and teratoma formation. Stem Cells express online
publication doi:10.1634/stemcells.2005-0393, March 23, 2006.
• 2006 Researchers turned embryonic stem cells into dopamine
producing cells, and when injected into rats with a Parkinson’s-like
condition, the rats showed improvement. However, in 100% of rats
the cells began to lose their specialization and grow uncontrollably.
All the animals showed indications of early tumor formation.
Roy N et al., Functional engraftment of human ES cell–derived
dopaminergic neurons enriched by coculture with telomerase-
immortalized midbrain astrocytes. Nature Medicine 12, 1259-68;
November 2006.

 A study by Instituto Brazzini Radiologos Asociados in Lima,A study by Instituto Brazzini Radiologos Asociados in Lima,
Peru, showed considerable improvement in Parkinson'sPeru, showed considerable improvement in Parkinson's
symptoms after stem cell implants. Doctors registered varioussymptoms after stem cell implants. Doctors registered various
degrees of beneficial changes in brains of all 47 patients withindegrees of beneficial changes in brains of all 47 patients within
one week of the treatment. A team of Dr. Augusto Brazzinione week of the treatment. A team of Dr. Augusto Brazzini
Armestar, the director of the institute, infusedArmestar, the director of the institute, infused autologous stemautologous stem
cells derived from bone marrowcells derived from bone marrow into the arteries that supplyinto the arteries that supply
blood to parts of brain that are typically damaged byblood to parts of brain that are typically damaged by
Parkinson's disease. The findings show a clinical recovery ofParkinson's disease. The findings show a clinical recovery of
extrapyramidal symptoms, which are maintained over time, asextrapyramidal symptoms, which are maintained over time, as
well as function recovery, representing a better metabolism ofwell as function recovery, representing a better metabolism of
neurons and better performance in the brain.neurons and better performance in the brain.
 Susman, Ed, "Stem Cell Implant to the Brain Helps ImproveSusman, Ed, "Stem Cell Implant to the Brain Helps Improve
Parkinson's Symptoms:Parkinson's Symptoms: Accessed at: ( 17 April 2008).Accessed at: ( 17 April 2008).
http://www.docguide.com/news/content.nsf/news/852571020057CCF6852574http://www.docguide.com/news/content.nsf/news/852571020057CCF6852574
1600511A241600511A24 <http://www.stemcellresearchfacts.org/parkinsons-disease/><http://www.stemcellresearchfacts.org/parkinsons-disease/>

 Stem cells were taken from patients' bones and were sent to theStem cells were taken from patients' bones and were sent to the
laboratory to be separated and purified. A team oflaboratory to be separated and purified. A team of
interventionists advanced a catheter from an incision into theinterventionists advanced a catheter from an incision into the
groin that gained access to the arterial system. From there, undergroin that gained access to the arterial system. From there, under
imaging guidance, the catheter was advanced through the carotidimaging guidance, the catheter was advanced through the carotid
artery, the posterior cerebral arteries, and the posteriorartery, the posterior cerebral arteries, and the posterior
communicating arteries. At that time, the stem cells were slowlycommunicating arteries. At that time, the stem cells were slowly
infused through the catheter into the arteries that irrigate theinfused through the catheter into the arteries that irrigate the
basal nucleus and the substantia nigra -- an area where neuronsbasal nucleus and the substantia nigra -- an area where neurons
are depleted in Parkinson's patients.are depleted in Parkinson's patients.
 To date, the team has implanted stem cells in 15 women and 30To date, the team has implanted stem cells in 15 women and 30
men. The average age of the patients was about 50 years;men. The average age of the patients was about 50 years;
Parkinson's disease had been diagnosed from 1 year to 18 yearsParkinson's disease had been diagnosed from 1 year to 18 years
before implantation. At the 1-week follow-up, 39 patients hadbefore implantation. At the 1-week follow-up, 39 patients had
achieved a 35% improvement as assessed by a battery ofachieved a 35% improvement as assessed by a battery of
Parkinson's disease validated tests. At the 1-month follow-up, 34Parkinson's disease validated tests. At the 1-month follow-up, 34
patients showed a 52% improvement. At 3 months, 23 patientspatients showed a 52% improvement. At 3 months, 23 patients
had improved an average of 59%; at 6 months, 6 patients hadhad improved an average of 59%; at 6 months, 6 patients had
improved 76%; after 12 months the 1 person to reach that levelimproved 76%; after 12 months the 1 person to reach that level
had achieved an 80% improvement (had achieved an 80% improvement (P P < .001).< .001).

• Pharmacological therapies are valuable but suffer from two
main drawbacks: side effects and loss of efficacy with disease
progression.
• Surgical treatment is no better than drugs.
• Transplantation of embryonic mesencephalic tissue has
emerged as a therapeutic alternative, but the unstable efficiency
and the shortage of embryonic donors limit its clinical
application.
• Recent advances in stem cell research inspire our hope that
stem cell transplantation to replace degenerated neurons may
be a promising therapy for Parkinson’s disease.
• There are three sources of stem cells currently in testing:
embryonic stem cells, neural stem cells, and mesenchymal stem
cells. The stem cell transplantation in the animal model of
Parkinson’s disease proves that it is capable of relieving
symptoms and restoring damaged brain function.

 Stem cell research seems to be promising in regeneratingStem cell research seems to be promising in regenerating
hope to cure Parkinson’s disease. This will motivatehope to cure Parkinson’s disease. This will motivate
innumerable patients across the world to explore this newinnumerable patients across the world to explore this new
modality. However we need to observe the long termmodality. However we need to observe the long term
clinical effects in large number of patients to decide its roleclinical effects in large number of patients to decide its role
in the treatment of the degenerative diseases.in the treatment of the degenerative diseases.
 Future stem cell research should focus not only onFuture stem cell research should focus not only on
improving the symptoms of P.D. but also onimproving the symptoms of P.D. but also on
neuroprotection that can favourably modify natural courseneuroprotection that can favourably modify natural course
and slow progression of the disease.and slow progression of the disease.

 To make these therapies more accessible and effective itTo make these therapies more accessible and effective it
will be important to improve clinical protocols and gene-will be important to improve clinical protocols and gene-
delivery vectors, and to gain a deeper understanding ofdelivery vectors, and to gain a deeper understanding of
stem cells.stem cells.
 The present challenge is to reduce the risk of suchThe present challenge is to reduce the risk of such
transplants and increase the number of patients who cantransplants and increase the number of patients who can
safely access this treatment. In developing countries,safely access this treatment. In developing countries,
such ‘one-shot’ treatments are highly desirable becausesuch ‘one-shot’ treatments are highly desirable because
chronic treatments are difficult to sustain.chronic treatments are difficult to sustain.

What happens next?
What everyone is anxious to know is, "What will happen
next in Parkinson's disease research?" Two critical goals are
to develop diagnostic approaches that allow early recognition
of PD and to find a way to slow the disease's progression.
The development of effective and safe cell therapies is of
critical importance, and scientists have multiple avenues to
explore that require intensive research.
A major challenge researchers face is getting the
transplanted DA embryonic stem cells to maintain their
new form in large numbers and over an extended period
of time without forming tumours.

I believe that we can
finally conquer our
diseases caused by all
abnormal organs , and
make our life long!
Nerve Stem Cell

AcknowledgementAcknowledgement
 Dr. (Mrs.) S. M. Vaidya,Dr. (Mrs.) S. M. Vaidya,
Prof. & Head*Prof. & Head*
 Dr.(Mrs.) N.V. Aundhkar,Dr.(Mrs.) N.V. Aundhkar,
Professor *Professor *
* Dept of Physiology,* Dept of Physiology,
B. J. Medical College, PuneB. J. Medical College, Pune

Stem cell research in Parkinson's Disease

• Current state of stem cell research for the treatment of Parkinson’s disease.
J Neurol (2002) 249 [Suppl 3]: III/33–III/35 DOI 10.1007/s00415-002-1307-y
Love SLove S et al., Glial cell line-derived neurotrophic factor induces neuronalet al., Glial cell line-derived neurotrophic factor induces neuronal
sprouting in human brain, Nature Medicine 11, 703-704, July 2005sprouting in human brain, Nature Medicine 11, 703-704, July 2005
Slevin JTSlevin JT et al., Improvement of bilateral motor functions in patients withet al., Improvement of bilateral motor functions in patients with
Parkinson disease through theParkinson disease through the unilateral intraputaminal infusion of glial cell line-unilateral intraputaminal infusion of glial cell line-
derived neurotrophic factor,derived neurotrophic factor, Journal of Neurosurgery 102, 216-222, February 2005Journal of Neurosurgery 102, 216-222, February 2005
Gill SS et al.; “Direct brain infusion of glial cell line-derived neurotrophic factor inGill SS et al.; “Direct brain infusion of glial cell line-derived neurotrophic factor in
Parkinson disease”; Nature Medicine 9, 589-595; May 2003 (published online 31Parkinson disease”; Nature Medicine 9, 589-595; May 2003 (published online 31
March 2003)March 2003)
 Factor S, Weiner W (eds): Parkinson's Disease: Diagnosis and Clinical
Management, 2d ed. New York, Demos Medical Publishing, 2007
 Hardy J et al: Genetics of Parkinson's disease and parkinsonism. Ann Neurol
60:389, 2006 [PMID: 17068789]
 Lippa CF et al: DLB and PDD boundary issues: Diagnosis, treatment, molecular
pathology, and biomarkers. Neurology 68:812, 2007 [PMID: 17353469]
 Schade R et al: Dopamine agonists and the risk of cardiac-valve regurgitation.
N Engl J Med 356:29, 2007 [PMID: 17202453]
 http://www.mit.edu/afs/athena/user/p/a/pandre/www/Neurology.html.

Stem cell research in Parkinson's Disease

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