Blood–brain barrier challenged by new drug delivery vehicle
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Newsdesk hypothesis, others do not. In particular, in the recent Women’s Health Initiative Memory Study HRT given to women aged 65 years or older was not beneficial. Indeed, there was evidence for increased incidence of dementia in women given HRT. “Given these contradictory results, we wondered whether brain concen- trations of oestrogen are more important rather than blood concen- trations “, says Li. “The brain can make its own oestrogen and this prod- uction might be upregulated when circulating concentrations drop.” The researchers measured oestrogen concentrations in post-mortem brain samples from ten women with AD and from ten matched controls. Total brain oestrogen in the women with AD was 60% of that in the control women. The researchers also crossed APP23 transgenic mice with mice that lacked aromatase, an enzyme needed for oestrogen synthesis. The oestrogen- deficient APP23 mice developed A plaques by 6 months old; control APP23 mice did not develop plaques until at least 9 months old and even then the plaques seemed to be smaller (Proc Natl Acad Sci USA 2005; 102: 19198–203). “These results strengthen the belief that oestrogen could protect against AD”, comments Victor Henderson (Stanford University, CA, USA), “but imply that the mechanisms of putative protection may be quite complicated”. One caveat about the animal study, notes Henderson, “is that there is some debate about the exact relationship between A deposition in the brain and Alzheimer symptoms”. “This is an interesting paper that, like any new insight, opens up many more questions for future studies”, adds Mark Smith (Case Western Reserve University, Cleveland, OH, USA), who also sounds a note of caution about the study. It will be important, he says, to test whether there are cognitive changes in the oestrogen-deficient APP23 mice that correlate with early A deposition. Jane Bradbury http://neurology.thelancet.com Vol 5 February 2006 117 Human neural progenitor cells (hNPC), genetically modified to release glycosylated glial cell derived neuro- trophic factor (GDNF), can be used to deliver the growth factor to the brain. This approach could represent a safe and viable option for delivering growth factors to specific targets within the CNS for diseases such as Parkinson’s. Neurodegenerative diseases are difficult to treat because of difficulties in getting drugs to penetrate the blood–brain barrier. Previous studies of GDNF in parkinsonian primates have shown that direct infusion into the ventricles resulted in a reversal of symptoms. Continuous infusions of GDNF directly into the caudal putamen of patients with Parkinson’s disease over 3 years have been shown to be safe and to significantly decrease symptoms. However, this method is complex and requires the use of very high concentrations of GDNF. Genetically modified hNPC, engine- ered to produce GDNF, have been assessed in a rat model of Parkinson’s disease and in elderly monkeys. The hNPC–GDNF cells were transplanted into the striatum of rats 10 days after the creation of a partial lesion of the dopamine system (Gene Therapy 2005; published online Dec 15. DOI:10.1038/ sj.gt.3302679). “In the animal model we could actually find increased numbers of the dopamine neurons, we could see increased fibre sprouting in the striatum, and the GDNF was transported from the striatum to the substantia nigra”, says study author Soshana Behrstock (University of Wisconsin, Madison, WI, USA). We also saw a trend towards behavioural recovery, she added, and at 3 months post-transplantation, the transplanted cells were surviving and expressing the protein. In a smaller study, three aged rhesus monkeys were transplanted with hNPC–GDNF into the putamen, and 3 months after transplantation the cells expressed high concentrations of GDNF. None of the animals in either study developed brain tumours. Behrstock cautions that this research is not yet ready for human trials. However, the study represents a useful step in determining whether hNPC or stem cells will be useful in treating neurodegenerative disorders, com- ments Mark Tuszynski (University of California, San Diego, CA, USA). “Many questions remain to be addressed before anticipating potential use in humans: will the cells support behavioural recovery? Must the cells be genetically modified to express a growth factor in order to provide beneficial effects?” Roxanne Nelson Blood–brain barrier challenged by new drug delivery vehicle Genetically modified cells could be Trojan horse for GDNF delivery Christian Darkin/Science Photo Library Rights were not granted to include this image in electronic media. Please refer to the printed journal.
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Transcript of Blood–brain barrier challenged by new drug delivery vehicle
Newsdesk
hypothesis, others do not. Inparticular, in the recent Women’sHealth Initiative Memory Study HRTgiven to women aged 65 years or olderwas not beneficial. Indeed, there wasevidence for increased incidence ofdementia in women given HRT.
“Given these contradictory results,we wondered whether brain concen-trations of oestrogen are moreimportant rather than blood concen-trations “, says Li. “The brain can makeits own oestrogen and this prod-uction might be upregulated whencirculating concentrations drop.”
The researchers measured oestrogenconcentrations in post-mortem brainsamples from ten women with ADand from ten matched controls. Total
brain oestrogen in the women with ADwas 60% of that in the control women.The researchers also crossed APP23transgenic mice with mice that lackedaromatase, an enzyme needed foroestrogen synthesis. The oestrogen-deficient APP23 mice developed A�plaques by 6 months old; controlAPP23 mice did not develop plaquesuntil at least 9 months old and eventhen the plaques seemed to be smaller(Proc Natl Acad Sci USA 2005; 102:19198–203).
“These results strengthen the beliefthat oestrogen could protect againstAD”, comments Victor Henderson(Stanford University, CA, USA), “butimply that the mechanisms ofputative protection may be quite
complicated”. One caveat about theanimal study, notes Henderson, “isthat there is some debate about theexact relationship between A�deposition in the brain and Alzheimersymptoms”.
“This is an interesting paper that,like any new insight, opens up manymore questions for future studies”,adds Mark Smith (Case WesternReserve University, Cleveland, OH,USA), who also sounds a note ofcaution about the study. It will beimportant, he says, to test whetherthere are cognitive changes in theoestrogen-deficient APP23 mice thatcorrelate with early A� deposition.
Jane Bradbury
http://neurology.thelancet.com Vol 5 February 2006 117
Human neural progenitor cells (hNPC),genetically modified to releaseglycosylated glial cell derived neuro-trophic factor (GDNF), can be used todeliver the growth factor to the brain.This approach could represent a safeand viable option for delivering growthfactors to specific targets within theCNS for diseases such as Parkinson’s.
Neurodegenerative diseases aredifficult to treat because of difficultiesin getting drugs to penetrate theblood–brain barrier. Previous studies ofGDNF in parkinsonian primates haveshown that direct infusion into theventricles resulted in a reversal ofsymptoms. Continuous infusions ofGDNF directly into the caudal putamenof patients with Parkinson’s diseaseover 3 years have been shown to besafe and to significantly decreasesymptoms. However, this method iscomplex and requires the use of veryhigh concentrations of GDNF.
Genetically modified hNPC, engine-ered to produce GDNF, have beenassessed in a rat model of Parkinson’sdisease and in elderly monkeys. ThehNPC–GDNF cells were transplantedinto the striatum of rats 10 days after
the creation of a partial lesion of thedopamine system (Gene Therapy 2005;published online Dec 15. DOI:10.1038/sj.gt.3302679).
“In the animal model we couldactually find increased numbers of thedopamine neurons, we could seeincreased fibre sprouting in thestriatum, and the GDNF wastransported from the striatum to thesubstantia nigra”, says study authorSoshana Behrstock (University ofWisconsin, Madison, WI, USA). We alsosaw a trend towards behaviouralrecovery, she added, and at 3 monthspost-transplantation, the transplantedcells were surviving and expressing theprotein.
In a smaller study, three aged rhesusmonkeys were transplanted withhNPC–GDNF into the putamen, and3 months after transplantation thecells expressed high concentrations ofGDNF. None of the animals in eitherstudy developed brain tumours.
Behrstock cautions that this researchis not yet ready for human trials.However, the study represents a usefulstep in determining whether hNPC orstem cells will be useful in treating
neurodegenerative disorders, com-ments Mark Tuszynski (University ofCalifornia, San Diego, CA, USA). “Manyquestions remain to be addressedbefore anticipating potential usein humans: will the cells supportbehavioural recovery? Must the cellsbe genetically modified to express agrowth factor in order to providebeneficial effects?”
Roxanne Nelson
Blood–brain barrier challenged by new drug delivery vehicle
Genetically modified cells could be Trojan horse for GDNF delivery
Chris
tian
Dar
kin/
Scie
nce
Phot
o Li
brar
y
Rights were not granted to include thisimage in electronic media. Please refer to
the printed journal.
