Treating Parkinson Disease with Adult Stem Cells

Henry E Young1*, Lee Hyer2, Asa C Black Jr3 and Joe Sam Robnson Jr!
1Professor, Regeneration Technologies, Macon, USA
2Professor, Georgia Neurological Institute, Macon, USA
3Professor, Memorial General Hosital!Uni"ersit# of South $arolina Me%ical School, Green"ille, USA
&Neurosurgeon, Georgia Neurological Institute, Macon, USA
Abstract
Parkinson disease affects ~2% of all people 7 !ears of age and older" People with Parkinson disease
e#hibit e#cessi$e shaking %tremors& at rest' loss of mental function' loss of in$oluntar! function' and
ps!chiatric problems" Aproposed e#perimental cure for Parkinson disease is the transplantation of health!
ner$e cells into the brain" (t hasbeen proposed that these ner$e cells be taken from either aborted fetuses
or deri$ed from embr!onic stem cells" Dueto ethical and moral issues that proposal will probabl! not
become a realit!" )ndogenous adult totipotent stem cells andadult pluripotent stem cells are $er! similar
to embr!onic stem cells" These primiti$e adult stem cells will form neurons'glia' skin' muscle' fat'
cartilage' bone' blood $essels' blood cells' li$er cells and pancreas cells under the appropriateinducti$e
conditions" The current report proposes the use of adult totipotent stem cells for the treatment of
Parkinsondisease" As a test of this proposal' adult totipotent stem cells were utili*ed in a bedside clinical
autologous phase+efficac! trial in adult humans with Parkinson disease" The results from this stud!
suggested an efficacious responseutili*ing adult totipotent stem cells as a treatment modalit! for
Parkinson disease
(ntroduction
Parkinson,s disease is a neurodegenerati$e condition that tends to present late in life" This condition is
characteri*ed b! the presenceof brad!kinesia' a resting tremor' and rigidit!" -arious degrees ofcogniti$e'
autonomic' and ps!chiatric abnormalities ma! also bepresent ./'20" Parkinson disease affects millions of
humans" (t is acommon neurodegenerati$e disease with a lifetime incidence of 2"1%and a pre$alence of at
least 2% in indi$iduals o$er 7 !ears of age ./0"This disease afflicts primaril! the dopaminergic neurons'
which ha$etheir cell bodies located in the substantia nigra pars compacta %S2pc&"These neurons send
a#ons to the caudate and putamen %collecti$el!known as the corpus striatum&" The progressi$e loss of
these cellsresults in the gradual decrease o$er time of striatal dopamine le$els'which in turn produces a
decrease in striatal output to the thalamus"These alterations result in a decrease in cortical motor output"
Thisdecrease can account for some of the obser$ed motor s!mptoms'especiall! brad!kinesia and rigidit!'
but other features such as aresting tremor probabl! ha$e a largel! non+dopaminergic
component.30"Patients can be effecti$el! treated with drugs that target thedopaminergic nigro+striatal
pathwa!' but o$er time the efficac! ofthese medications is limited b! the de$elopment of profound
motorfluctuations and d!skinesias ./0" At this stage of the disease othertherapies are often re4uired'
including deep brain stimulation"5owe$er' all these treatments are onl! s!mptomatic and do little tohalt
or re$erse the progression of the disease ./0" Therapies that actuall!cure patients of Parkinson disease are
still not a$ailable' but cell basedtherapies offer e#citing possibilities ./'60" 2eural transplantation as
atreatment modalit! for Parkinson disease is based on a well+definedbiological mechanism7 reco$er! of
function following the restorationof dopaminergic transmission in the corpus striatum" 8ind$all
.60proposed that four different cellular sources could be used to formdopaminergic neurons for neural
transplantation for Parkinsondisease7 %a& embr!onic stem cells from a fertili*ed egg9 %b& neural stemcells
from an embr!onic brain9 %c& neural stem cells from an adultbrain9 or %d& stem cells from other tissues"
The crucial issue is whether the transplanted cells would form functional dopaminergic
neurons'regardless of the source of the stem cells .60"(n a pre$ious animal stud! we chose to e#amine the
effects oftransplanting a 8ac+: genomicall! labeled na;$e pluripotent stem cellclone .10 deri$ed from
skeletal muscle into the brains of adult rats thathad been lesioned with <+h!dro#!dopamine .<'70" (n the
followingclinical phase+ efficac! trial we chose to e#amine the effects ofinfusing autologous totipotent
and pluripotent stem cells .=0 intothe brains of indi$iduals with Parkinson disease" The science behindour
bench+top animal stud! and bedside clinical stud! is multi+fold">oung et al" .?0 reported the isolation and
single cell cloning of adult+deri$ed pluripotent stem cells from the connecti$e tissue stroma ofmultiple
organs in animals and humans" The! demonstrated thata clonal population of adult+deri$ed pluripotent
cells was capableof ob@ecti$el! forming <3 of the 22A possible cells of the bod!'including multiple t!pes
of neurons' oligodendroc!tes' astroc!tesand capillaries" >oung and Black .=0 reported the isolation' single
cellcloning' and characteri*ation of adult+deri$ed totipotent stem cellsfrom the connecti$e tissue stroma
of multiple organs in animals andhumans" The! demonstrated that a clonal population of these stemcells
was capable of ob@ecti$el! forming << of the 22A possible cellsof the bod!' including multiple t!pes of
neurons' oligodendroc!tes'astroc!tes' capillaries and spermatogonia" Cnfortunatel!' at the timethese
studies were performed we onl! had assa!s to detect << of the2A possible cells in the bod!" Therefore'
the limited number ofcell t!pes anal!*ed was due to the paucit! of ob@ecti$e assa!s ratherthan the
absolute number of differentiated cell t!pes that these stemcells would form" Dhen in@ected into an
animal' the totipoten stem cells would home to damaged tissue sites and onl! replace thedamaged tissues"
These studies occurred in rodent models of inducedm!ocardial infarction and induced Parkinson disease
.=+/0" >ounget al" also demonstrated that the single cell clonal populations ofpluripotent stem cells and
totipotent stem cells would maintain anormal kar!ot!pe after multiple cell doublings .7'='//0 and
couldincrease these stem cells circulating in the peripheral blood b! trauma./20' moderate e#ercise
./3'/60 and ingestion of a c!anobacter ./3'/60
The c!anobacter ETAFA %Table /& %Eegeneration Technologies'Gacon' HA&' was e#amined in e4uines
with respect to its abilit! tostimulate the endogenous production of primiti$e adult stem cells"The results
suggested that ETAFA stimulated the proliferation andre$erse+diapedesis of e#cess adult stem cells into
the peripheral$asculature where the adult stem cells could be easil! har$ested'isolated and counted
%Figure /& ./3'/60"To date' we ha$e been able to stimulate an increase in 4uantit!of adult totipotent stem
cells and adult pluripotent stem cells in anindi$idual,s $asculature using ETAFA' thus making the
indi$idualtheir own bioreactor for generating e#cess adult stem cells forhar$est and subse4uent use" The
autologous adult totipotent stemcells and autologous adult pluripotent stem cells were har$ested
$ia$enipuncture and the primiti$e stem cells separated from the bloodelements" The primiti$e stem cells
were rinsed to remo$e serumproteins and pristine autologous adult totipotent and adult pluripotentstem
cells were transfused in a safe and efficient manner within a twoda! period ./6'/10" The current phase+
efficac! stud! was intended to$erif! these results using a targeted number of sub@ects with
ob@ecti$eassa!s"Finall!' we note that ultimatel! there ma! be better methodsfor the introduction of stem
cells to b!pass the blood+brain barrierto efficientl! impro$e motor outcomes" De ha$e one non+
in$asi$etechni4ue and two in$asi$e techni4ues to allow stem cells entranceinto the sub+arachnoid cisterns
of the central ner$ous s!stem" Thefirst techni4ue is intra+nasal infusion ./<0 of the primiti$e
totipotentstem cells into the superior nasal ca$it!' where the! tra$el betweenthe olfactor! epithelial cells'
along the olfactor! processes' throughthe cribiform plate' and tra$el along the olfactor! ner$es to enter
thesubarachnoid cisterns of the brain without tra$ersing the blood+brainbarrier ./10"The two in$asi$e
procedures in$ol$e either intrathecal in@ection%re$erse spinal tap& or stereotactic in@ections" (ntrathecal
in@ection" allow the primiti$e stem cells to ph!sicall! b!pass the blood+brainbarrier' migrate into the
subarachnoid spaces of the spinal cord andtra$erse to the appropriate damaged neuronal sites"
Cnfortunatel!'this techni4ue creates scar tissue at the site%s& of in@ection" Stereotatcticin@ection is direct
in@ection of primiti$e stem cells into the lesion site'after remo$ing portions of the scalp and boring holes
in the cranium./70" The stereotactic in@ection procedure also ph!sicall! b!passes theblood+brain barrier'
but is considered ma@or surger! and performedunder general anesthesia" For the clinical stud! reported
herein wechose the least in$asi$e and most tolerated techni4ue !et a$ailable tous' intra+nasal infusion ./<0
of adult totipotent stem cells" Gaterials and Gethods The use of humans in this stud! complied with the
guidelines ofThe Gedical Center of Central Heorgia (n$estigational Ee$iew Board%GCCH+(EB&" These
guidelines reflect the criteria for humane humancare of the 2ational Eesearch Council prepared b! the
(nstitute of5uman Eesources and published b! the 2ational (nstitutes of 5ealth" Stud! ob@ecti$es The
o$erall ob@ecti$e of this stud! was to mobili*e autologous adulttotipotent and pluripotent stem cells into
the blood stream in situ atsufficient le$els to pro$ide a continual source of autologous adult stemcells for
cell' tissue' and organ+associated Parkinson repair" De useda Parkinson disease %PD& population" De
targeted first the motorchanges in these patients' as well as assessed the o$erall impro$ementof cognition'
affect' function' ad@ustment' and caregi$er burden"
Criteria to assess Parkinson sub@ects for inclusion
/" Sub@ects meeting Iueen,s S4uare Criteria for Parkinson disease"
2" 2o signs of more e#tensi$e neurodegeneration indicatingat!pical Parkinsonism"
3" A positi$e response to le$odopa or dopamine agonist"
6" Sub@ects aged <+=1 !ears"
1" Sub@ects must ha$e completed at least the ?th grade and be fluentin )nglish"
<" Ps!chotropic medications will be allowed if the sub@ect hasbeen on a stable dose for at least one month"
7" Ben*odia*epines will be allowed if taken during the da! prior to<7 pm and not taken as a sleep aid"
=" Parkinson disease sub@ects will not currentl! be e#periencingdementia %DSG+(- criteria&"
?" Presence of a caregi$er"
/" GGS) 2 or greater"
Criteria to assess Parkinson sub@ects for e#clusion
/" Sub@ects taking Coumadin %Darfarin&" %There is appro#imatel!23 micrograms of $itamin+J per capsule
of AFA %Table /& that has thepotential to interfere with the anti+coagulation action of
Coumadin"Therefore' we will lea$e the decision to e#clude the sub@ect from the trial in the hands of the
Sub@ect,s own ph!sician&
"2" Sub@ects with se$ere hepatic impairment"
3" Sub@ects with se$ere CKPD"
6" Sub@ects e#ceedingl! frail based on multiple s!stems criteria %as determined b! Dr" Eobinson&
"1" Sub@ects with galactorrhea"
<" Sub@ects with prolactin sensiti$e tumors"
7" Parkinsonism due to Parkinson,s+plus diagnoses or tomedication
=" Sub@ects with a communicable disease' i"e"' 5(-' 5epatitis' etc"
?" Sub@ects ha$ing deep brain stimulation"2umber of sub@ectsSub@ects who met inclusionLe#clusion
criteria were admitted"Based on other studies with PD patients in this area with sleep ./=0 wee#pect /%
dropout" De enrolled / participants and their caregi$er
S"udy desgn
This is a Phase MN Clinical (nter$ention Trial with adult totipotentand pluripotent stem cellsOFirst in
Parkinson disease patients"Baseline ratings on outcome measures will ser$e as control $alues" Attime *ero
%Pre+Screen&' before start of ingestion of ETAFA to makethemsel$es their own sterile bioreactors for the
propagation andre$erse diapadesis of autologous totipotent stem cells and autologouspluripotent stem
cells' / out of / sub@ects were gi$en a code number%P,s from /O/&' and screened for age' gender'
marital status' andeducation %Table 2&" The ten $olunteers were then scored for C(BC'CPD+total' 5oehn+
>ahr' )SS+Total' FAI+Total' and BD(+Total' as wellas cognition and caregi$er burden %Tables 6+/3& %see
references below&"At the end of three months of ingestion of ETAFA a second set of testswas performed"
Two test sub@ects' P,s 6 and =' dropped out of the stud!before the second set of testing was performed"
This left = participant in the stud!"
The participants then underwent intra+nasal and intra$enous infusion of autologous totipotent
stem cells and pluripotent stem cells" This was accomplished b! withdrawing 6 milliliters of
whole blood and placing the blood into )DTA+containing /+ml hemo$ac tubes %BD Sciences&"
Subse4uent processing of the blood was performed using uni$ersal precautions" The tubes were
in$erted se$eral times mi# the whole blood with the )DTA and then the tubes were placed
upright into a tube holder and placed into a 6oC refrigerator for 6= hours" During this time period
the blood elements %red blood cells' white blood cells and platelets& separated from the serum
and totipotent stem cells and pluripotent stem cells b! gra$it!" After 6= hours the hemo$ac tubes
containing the separated cellular elements were spra!ed with 7% alcohol and placed within a
C-Lalcohol+sterili*ed Class+(( 5)PA+filtered Biosafet! cabinet" The serum was remo$ed from
the tubes and placed into sterile /1+ml pol!prop!lene tubes %Falcon&" The hemo$ac tubes were
spra!ed with 7% alcohol and placed into bioha*ard bags for disposal" The serum was then
processed for stem cell separation" The /1+ml tubes were spun at 1 rcf %relati$e centrifugal
force& to pellet the larger pluripotent germ la!er lineage stem cells" After remo$al from the
centrifuge the outside of the tubes were spra!ed with 7% alcohol and placed inside the Class+((
Biosafet! hood" The supernatant was decanted to a second set of sterile /1+ml tubes and the
tubes centrifuged at 6' rcf to pellet the remaining totipotent stem cells and pluripotent stem
cells" The supernatant was remo$ed and discarded" The cell pellets were reconstituted in /+ml
$olumes of sterile saline and pooled' using sterile techni4ue" The tubes containing the suspended
cells were spun a second time at 6' rcf to pellet the stem cells' washed with /+ml $olume of
sterile saline' 7 tubes pooled at each wash step' and 7 ml of sterile saline added to each tube'
using sterile techni4ue" At each pooling the cells were spun at 6' rcf to pellet the totipotent
and smaller pluripotent stem cells and separate the stem cells from their serum" These multiple
washLpooling procedures were performed to wash awa! an! residual serum proteins adhering to
the stem cells" The participants were prepared for intra+nasal infusion of totipotent stem cells and
pluripotent stem cells as follows" )ach participant was asked to clean out their nasal passages b!
inhaling $olumes of sterile "<1% saline solution %Kcean& and then blowing nasal contents into
sink" This was repeated 3+6 times to insure loss of stick! mucus from the inside of the nasal
passages" The participant was then placed in the supine position with their head lower than their
bod! %modified Trendelenberg position&' with their nostrils pointing upward" Stem cells
suspended in sterile saline were dropped %$ia /+ccs!ringe barrel& into each nostril onto the
olfactor! epithelium" After administering the stem cells the participant was asked to remain in
that position for 1 minutes to insure the deposition of the stem cells on the olfactor! mucosa with
migration through the mucosa' along the olfactor! processes' through the cribriform plate' to the
olfactor! bulb' and posteriorl! along the olfactor! ner$es to gain entrance past the blood+brain
barrier and to the subarachnoid cisterns of the brain and spinal cord" After fi$e minutes each
participant was helped to the sitting position and allowed to remain in that position for 3
minutes to ad@ust for $ertical e4uilibrium" Test sub@ects were then assessed at regular inter$als"
This occurred at baseline' and three months post baseline %prior to the intra+nasal infusion of
autologous adult totipotent and pluripotent stem cells& %MpreM&' and at 2 weeks %MpostN& and four
months post procedure %Mpost+postN&"
#arknson assessmen" cr"era
Participants were e$aluated in the following wa!s" De e$aluated participants at the abo$e
mentioned inter$als" De also assessed caregi$ers at three month inter$als" The areas that are
targeted include the following Parkinson Assessment Criteria7
%/& Gotor Q CPDES+((( ./?09
%2& Cognition Q Trail Gaking Part A and B .209
%3& Affect Q Beck Depression Scale+(( %BD(+((& .2/09
%6& Function Q Functional Assessment Iuestionnaire %FAI& .220'
Schwab and )ngland disabilit! scale .230 and 5oehn+>ahr Scale
.2609
%1& Sleep7 )pworth Sleepiness Scale %)SS& .2309
%<& K$erall clinical impro$ement with the C(B(C+Plus %Clinician,s
(nter$iew+Based
(mpression of Change Plus Caregi$er (nput&9 and
%7& Caregi$er7 :arit Burden Scale .210"
Prior to stud! entrance' each patient underwent9 /& chart re$iew for medication regimen' medical
conditions' and laborator! $alues' 2& ph!sical e#amination and 3& diagnostic dementia
e$aluations completed b! the in$estigators" De also applied a Gini Gental State )#am %GGS)&
.2<0 at entr! to assure le$el of possible dementia and competence" Scores must be 2 or greater
to assure le$els of mild dementia or better' assuring at a minimum abilit! to fill out
4uestionnaires" (nformed consent was obtained from all willing participants using a Gedical
Center of Central Heorgia (nstitutional Ee$iew Board appro$ed consent form" (n the e$ent of
guardianship' consent was obtained from the guardian as well" The stud! population in$ol$ed
sub@ects with PD diagnosed b! Iueen S4uare criteria" All sub@ects were taking le$odopa or
dopamine agonists' or both" The! ma! be on other medications' including cholinesterase
inhibitors" All eligible candidates had a Godified 5oehn+>ahr Staging 2 %bilateral disease& to 6
%Se$ere Disabilit!&' as well as an GGS) of 2 or greater" There were sub@ects with medical co
morbidities as well as other complications %e"g"' ps!chiatric histor!' li$ing situations' poor life
habits' etc"&" The use and amount of ETAFA capsules is more in$ol$ed" A standard dosing
regimen as described b! Eegeneration Technologies was followed unless contraindicated b!
changes in the PD participant,s e$aluation criteria" At baseline all participants were measured
without taking the compound" After initial measurementswere taken the sub@ects were started on
one capsule containing 1 mg of ETAFA" Knl! three ETAFA capsules were taken throughout
the duration of the stud!" (n addition' at baseline % months& and at inter$als discussed abo$e' the
participants and their caregi$ers were e$aluated" Sub@ects were e$aluated for clinical
impro$ement from baseline" De also measured burden of caregi$ers b! the :arit Burden Scale
.210" De note too that we were attenti$e to safet! issues" De were especiall! attenti$e to PT'
PTT and (2E' issues related to coagulation"Descripti$e statistics are pro$ided" The primar!
target was the CPDES+((( o$er the time period of se$en months as the end point" Caregi$er
responses were also part of this secondar! anal!sis"
Resul"s
There were / sub@ects at the start of the trial and two dropped out" The a$erage age was <7'
education was @ust abo$e high school and there were 7 males and 3 females %Table 2&" The
a$erage GGS) was 2<"=' normal" De honed in on the salient $ariables for PD' for cognition' for
depression' for sleep' and for ad@ustment %Tables 3+/2&" K$erall' the participants showed a
$ariable pattern" Eegarding o$erall ratings in all areas %C(B(C&' the sub@ects went from a standard
baseline of 6" to 3"=' a slight impro$ement %Table 3&" This scale rates the person on mental
issues' beha$ior' and functioning" The ratings then went from moderatel! ill to mildl! ill"
Eegarding PD+specific problems' we applied the 5oehn+>ahr %Table 6&' the Schwab )ngland
%Table 1& and the o$erall PD rating of the CPDES %Table <&" )ach of these was measured at pre'
post and post+post onl!" All three showed little change" (n effect' the le$el of PD s!mptoms and
staging remained similar throughout the stud! period of 7 months" De had a measure for o$erall
ad@ustment' FAI %Table 7&" Throughout the entire time period of the stud! the sub@ects actuall!
got slightl! worse o$er timeO<"2 to ="" 2e#t we considered affect and sleep" De used the BD(+((
and )SS" From pre+pre to post+post these two $ariables showed minor changes" Sleep got better9
depression got slightl! worse" The numbers' howe$er' were $er! similar o$er the course of the
stud!" Sleep scores impro$ed from / %insomnia problems& to 7"6 %normal area&9 depression
scores remained below / %normal& %Tables = and ?&" De assessed cognition" De used the Trials
A and B as markers of this area %Table / and //&" These are measures of speed of processing
and e#ecuti$e functioning" (n general' the scores were poor' /+3 standard de$iations lower than
normal" Trails A got progressi$el! worse o$er time9 Trials B got worse at the last three measure
periods" Cognition as measured b! these markers did not impro$e" Finall!' we assessed caregi$er
ratings' :arit Burden Scale %Table /2& .210" 5ere sub@ects impro$ed slightl! o$er the stud! time
frame" The initial rating was 26 and the last three were ~2" Caregi$ers saw the sub@ects as
slightl! better" De present two figures with all the $alues for the indi$idual patients" De chose a
table of the CPDES %Figure 2& and FAI %Figure 3& as ke! markers for PD and ad@ustment" (n
sum' there was much CPDES
$scusson
Parkinson disease affects ~2% of all people 7 !ears of age and older" People with Parkinson
disease e#hibit e#cessi$e shaking %tremors& at rest' loss of mental function' loss of in$oluntar!
function' and ps!chiatric problems" A proposed e#perimental cure for Parkinson disease is the
transplantation of health! ner$e cells into the brain .60" (t has been proposed that these ner$e
cells be taken from either aborted fetuses or deri$ed from embr!onic stem cells .60" Due to
ethical and moral issues' that proposal will probabl! not become a realit!" Adult totipotent stem
cells and adult pluripotent stem cells are $er! similar to embr!onic stem cells in that the! ha$e
the capabilit! to form multiple cell t!pes' i"e"' neurons' interneurons' astroc!tes'
ligodendroc!tes' keratinoc!tes' skeletal muscle' cardiac muscle' smooth muscle' unilocular fat
cells' multilocular fat cells' h!aline cartilage' articular cartilage' growth plate cartilage' elastic
cartilage' fibrocartilage' endochondral bone' intramembranous bone' endothelial cells'
capillaries' arteries' $eins' l!mphatics' hematopoietic cells' gastrointestinal enteroc!tes'
hepatoc!tes' o$al cells' bile canalicular cells' biliar! cells' pancreatic ductal cells' glucagon
secreting R+cells' insulin+secreting S+cells' somatostatin+ secreting T+cells' etc"' under the
appropriate inducti$e conditions .7'/'/6'/70" The current report proposed the use of adult
totipotent stem cells and adult pluripotent stem cells for the treatment of Parkinson disease"
Bench top and bedside model s!stems were e#amined" A 8ac+: transfected clonal population of
adult pluripotent stem cells .?0 was utili*ed in a bench+top <+h!dro#!dopamine+induced niagral+
lesioned midbrain allogeneic animal model ./70" Eesults from the animal stud! demonstrated
replacement of dopaminergic neurons in the area of the <+K5DA lesion as well as replacement
of damaged neuronal cells' damaged neuronal supporti$e cells and damaged $ascular structures
caused b! the needle in@ections" A second test of this proposal in$ol$ed an autologous clinical
phase+ efficac! trial in adult humans with Parkinson disease" The results from the clinical stud!'
utili*ing the intra+nasal infusion of autologous adult totipotent stem cells' showed that some
patient,s outcome measures decreased n $alues %21%&' there was considerable stabilit! in some
patient,s outcome measures %1%& and some patient,s outcome measures increased in $alues
%21%&" The results from both studies suggested an efficacious response utili*ing adult stem cells
as a potential treatment modalit! for Parkinson disease" Dhile the goal of disease modification
for Parkinson disease is reasonabl! clear' the task of determining whether a therap! is disease
modif!ing is less clear" The underl!ing pathogenesis of Parkinson disease is not full! understood
and' therefore' de$eloping new disease modif!ing therapies remains difficult" The ultimate idea
is to MneuroprotectN and' in so doing' to interfere with the underl!ing pathogenic mechanism of
nigral cell death andLor rescue damaged but still $iable cell neurons" The motor and non+motor
s!mptoms of this disease presumabl! would be arrested and possibl! re$ersed if stem cells were
utili*ed" From a broad perspecti$e' the use of putati$e neuroprotecti$e factors %with or without a
known s!mptomatic effect& is critical in an understanding of Parkinson disease" (n the recent
past' with the possible e#ception of the ADAH(K trial .270' ma@or Parkinson disease studies' e"g"'
)88DKPA .2=0' DATATKP .2?0' and T)GPK .30 ha$e failed to conclusi$el! demonstrate a
neuroprotecti$e effect" Stem cells show the promise to be neuroprotecti$e" (n the current clinical
phase+ efficac! trial we accessed a group of PD patients at mid+le$el in the disease process"
There was much $ariabilit! and use of a stem cell model that can be impro$ed upon" De belie$e
now that we ha$e the resources to conduct such a stud!' a carefull! designed program to assess
this' and ha$e the fle#ibilit! to see its neuroprotecti$e $alue" Eesults would be e#ceedingl!
informati$e and we could proceed to further clinical trials" Kne promising a$enue in the hunt for
a remission in Parkinson disease s!mptoms does in$ol$e cell replacement therap!" Stem cells are
a source for cell replacement therap! due to their abilit! to self+ renew and their inherent
plasticit! that allows them to generate $arious t!pes of cells from a single cell" There are two
a$enues of adult stem cell therap! that could be used for neurological diseases such as Parkinson
disease' i"e"' allogeneic stem cell therap! or autologous stem cell therap!" )ither can be utili*ed
currentl! if minimal manipulati$e procedures are used to deri$e the cells" Cnfortunatel!' both
ha$e their ad$antages and disad$antages" Allogeneic stem cells ac4uired from a donor%s& that do
not carr! mutations for serious andLor life+threatening familial diseases could replace cells
carr!ing a genetic mutation causing the disease" 5owe$er' unpublished studies from our lab
suggest that matching genders as well as ABK groups and Eho+D positi$e or Eho+D negati$e
must be taken into consideration when transplanting allogeneic stem cells" Kur studies
demonstrated that gender mismatch will cause long+term problems in the indi$idual' i"e"' male
stem cells do not perform as e#pected when placed into an estrogen+progesterone+rich
en$ironment and female stem cells do not perform as e#pected when placed into a testosterone+
rich en$ironment" Similarl!' matching of blood groups is essential for maintenance of donor cell
longe$it! in the recipient" De would propose that since adult totipotent stem cells and adult
pluripotent stem cells ha$e the capabilit! to make hematopoietic cells .?'/'/60' that a few of
these transplanted stem cells could find their wa! to the bone marrow of the recipient and form
hematopoietic cells with cell surface markers of the donor" (f the allogeneic cells were
mismatched to the recipient' the recipient,s immune s!stem would likel! recogni*e the
differentiated cells as non+self and mount an inflammator! response against the Upercei$ed,
in$ading cells" Antibod! production b! B+cells and plasma cells along with opsini*ation and
phagoc!tosis of the in$ading cells b! macrophages would potentiall! decrease the total number
of donor cells a$ailable /'/6'/70" The adult stem cell' a postnatal cell that has the abilit! for
essentiall! unlimited population doublings and the abilit! to form an! cell t!pe below its lineage
placement .='/60' is one of the ke! elements in regenerati$e medicine" )le$en species of
mammals' including humans' possess their own endogenous highl! plastic na;$e adult stem cells'
i"e"' totipotent stem cells' pluripotent stem cells and multipotent stem cells .<+/'/6'/7'33'36'0"
Adult totipotent stem cells .='/60 and adult pluripotent stem cells .?'/'/60' either allogeneic or
autologous' are as highl! plastic as embr!onic stem cells .310 or iPS cells .3<0' but differ from
them in two $er! crucial wa!s" 2a;$e adult totipotent stem cells and na;$e adult pluripotent stem
cells will not spontaneousl! differentiate in the absence of inducti$e inhibitor! agents %such as
leukemia inhibitor! factor or anti+differentiation factor& in culture and the! will not form
teratomas %uncoupled embr!onic de$elopment& when transplanted into an indi$idual %Table /3&
.<'=+/'/6'/70" (n addition' since adult totipotent stem cells and adult pluripotent stem cells .=+
/'/60' either allogeneic or autologous' are not deri$ed from embr!onic cells or aborted fetal
tissues' the! make e#cellent candidates for regenerati$e medicine as highl! plastic transplantable
cells that are ideal for the repair and restoration of a multitude of damaged tissues
.1'<'?'/'/6'/70"
Ackno%ledgemen"s
The authors would like to thank Dr" Christina 8" Ga!$ille'
Dr" Gargaret Bolt@a'
Dr" Daniel Eo!al' Ciera Scott' 8aura GcJen*ie' Vulie A"
Collins' H!ps! 8ong
Black and Seth D!al for their technical assistance" This
research was supported
b! grants from Eub!e E!le Smith Charitable Trust %5)>&'
8ucille G" and 5enr! K"
>oung )state Trust %5)>& and GedCen Communit!
5ealth Foundation"
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