Possible Future Treatment for Parkinson’s Possible 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 1817 First 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 at Affects 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 When most people reach for a pen, their body acts in one

smooth and controlled movement. The instant a person thinks smooth and controlled movement. The instant a person thinks

of grabbing the pen, a series of nerve cells fire in an of grabbing the pen, a series of nerve cells fire in an

orchestrated symphony from the brain to the muscles orchestrated symphony from the brain to the muscles

responsible for that action.responsible for that action.

For the movement to be precise and smooth, all the nerve cells For the movement to be precise and smooth, all the nerve cells

in the “grabbing-the-pen network” must function properly, in the “grabbing-the-pen network” must function properly,

including cells that tell unneeded muscles to stay still.including cells that tell unneeded muscles to stay still.

In Parkinson’s disease (P. D.) the brain cells responsible for In Parkinson’s disease (P. D.) the brain cells responsible for

keeping unneeded muscles from moving keeping unneeded muscles from moving degeneratedegenerate and and diedie. .

That is in P. D. nerve cells that make the chemical That is in P. D. nerve cells that make the chemical dopaminedopamine

die. This results in progressively more dramatic and die. This results in progressively more dramatic and

uncontrolled movements, tremors, and spasms. uncontrolled movements, tremors, and spasms.

To date, there is no cure for P. D. because no one has figured To 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 out a way to bring back the specialized nerve cells that have

died.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 PDParkinson‘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 disease Signs 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 mouse 2002 Researchers injected Parkinson’s rats with mouse

embryonic stem cells. The rats showed a modest benefit for just embryonic stem cells. The rats showed a modest benefit for just

over 50% of the rats, but one-fifth (20%) of the rats died of brain over 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 functional Embryonic 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.

2003 2003 DopaminergicDopaminergic neurons made from mouse embryonic stem neurons made from mouse embryonic stem

cells were transplanted into Parkinson's mice and provided some cells were transplanted into Parkinson's mice and provided some

decrease in symptoms, but 20% of mice receiving the embryonic decrease 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 the Potential use of embryonic stem cells for the

treatment of mouse Parkinsonian models: improved behavior by treatment of mouse Parkinsonian models: improved behavior by

transplantation of in vitro differentiated dopaminergic neurons from transplantation 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. Some into neural progenitors and transplanted these into rats. Some

cells made dopamine, but the cells stopped growing at 12 cells made dopamine, but the cells stopped growing at 12

weeks. The rats exhibited a partial improvement in behavioral weeks. 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 Parkinsons derived 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 cells 2005 A Japanese team turned monkey embryonic stem cells

into neural stem cells. They transplanted these into monkeys into neural stem cells. They transplanted these into monkeys

with artificially induced Parkinsons’s, and some cells turned into with artificially induced Parkinsons’s, and some cells turned into

dopamine producing cells. There was mild alleviation of dopamine producing cells. There was mild alleviation of

symptoms. symptoms. Yasushi Takagi et al., Yasushi Takagi et al., Dopaminergic neurons generated Dopaminergic neurons generated

from monkey embryonic stem cells function in a Parkinson primate from monkey embryonic stem cells function in a Parkinson primate

model.model.

The Journal of Clinical Investigation 115 (1): January 2005.The Journal of Clinical Investigation 115 (1): January 2005.

• 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's Peru, showed considerable improvement in Parkinson's

symptoms after stem cell implants. Doctors registered various symptoms after stem cell implants. Doctors registered various

degrees of beneficial changes in brains of all 47 patients within degrees of beneficial changes in brains of all 47 patients within

one week of the treatment. A team of Dr. Augusto Brazzini one week of the treatment. A team of Dr. Augusto Brazzini

Armestar, the director of the institute, infused Armestar, the director of the institute, infused autologous stem autologous stem

cells derived from bone marrowcells derived from bone marrow into the arteries that supply into the arteries that supply

blood to parts of brain that are typically damaged by blood to parts of brain that are typically damaged by

Parkinson's disease. The findings show a clinical recovery of Parkinson's disease. The findings show a clinical recovery of

extrapyramidal symptoms, which are maintained over time, as extrapyramidal symptoms, which are maintained over time, as

well as function recovery, representing a better metabolism of well 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 Improve Susman, 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/852571020057CCF68525741600511A24  1600511A24  <http://www.stemcellresearchfacts.org/parkinsons-disease/> <http://www.stemcellresearchfacts.org/parkinsons-disease/>

Stem cells were taken from patients' bones and were sent to the laboratory to be Stem cells were taken from patients' bones and were sent to the laboratory to be separated and purified. A team of interventionists advanced a catheter from an separated and purified. A team of interventionists advanced a catheter from an incision into the groin that gained access to the arterial system. From there, under incision into the groin that gained access to the arterial system. From there, under imaging guidance, the catheter was advanced through the carotid artery, the imaging guidance, the catheter was advanced through the carotid artery, the posterior cerebral arteries, and the posterior communicating arteries. At that time, posterior cerebral arteries, and the posterior communicating arteries. At that time, the stem cells were slowly infused through the catheter into the arteries that irrigate the stem cells were slowly infused through the catheter into the arteries that irrigate the basal nucleus and the substantia nigra -- an area where neurons are depleted in the basal nucleus and the substantia nigra -- an area where neurons are depleted in Parkinson's patients.Parkinson's patients.

To date, the team has implanted stem cells in 15 women and 30 men. The average To date, the team has implanted stem cells in 15 women and 30 men. The average age of the patients was about 50 years; Parkinson's disease had been diagnosed age of the patients was about 50 years; Parkinson's disease had been diagnosed from 1 year to 18 years before implantation. At the 1-week follow-up, 39 patients from 1 year to 18 years before implantation. At the 1-week follow-up, 39 patients had achieved a 35% improvement as assessed by a battery of Parkinson's disease had achieved a 35% improvement as assessed by a battery of Parkinson's disease validated tests. At the 1-month follow-up, 34 patients showed a 52% improvement. validated tests. At the 1-month follow-up, 34 patients showed a 52% improvement. At 3 months, 23 patients had improved an average of 59%; at 6 months, 6 patients At 3 months, 23 patients had improved an average of 59%; at 6 months, 6 patients had improved 76%; after 12 months the 1 person to reach that level had achieved had improved 76%; after 12 months the 1 person to reach that level had achieved an 80% improvement (an 80% improvement (P P < .001). < .001). ttp://www.docguide.com/news/content.nsf/news/852571020057CCF68525741600511A24> ttp://www.docguide.com/news/content.nsf/news/852571020057CCF68525741600511A24>

• 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 regenerating hope to Stem cell research seems to be promising in regenerating hope to

cure Parkinson’s disease. This will motivate innumerable patients cure Parkinson’s disease. This will motivate innumerable patients

across the world to explore this new modality. However we need to across the world to explore this new modality. However we need to

observe the long term clinical effects in large number of patients to observe the long term clinical effects in large number of patients to

decide its role in the treatment of the degenerative diseases. decide its role in the treatment of the degenerative diseases.

Future stem cell research should focus not only on improving the Future stem cell research should focus not only on improving the

symptoms of P.D. but also on neuroprotection that can favourably symptoms of P.D. but also on neuroprotection that can favourably

modify natural course and slow progression of the disease.modify natural course and slow progression of the disease.

To make these therapies more accessible and effective it To 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 of delivery vectors, and to gain a deeper understanding of

stem cells.stem cells.

The present challenge is to reduce the risk of such The present challenge is to reduce the risk of such

transplants and increase the number of patients who can transplants 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 because such ‘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

• 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-yLove S Love S et al., Glial cell line-derived neurotrophic factor induces neuronal et 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 2005Slevin JT Slevin JT et al., Improvement of bilateral motor functions in patients with et al., Improvement of bilateral motor functions in patients with Parkinson disease through the Parkinson 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 2005Gill SS et al.; “Direct brain infusion of glial cell line-derived neurotrophic factor in Gill 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 31 Parkinson 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.