LUND UNIVERSITY

PO Box 117221 00 Lund+46 46-222 00 00

Stable, long-term label opens doors for gene therapy.

Lundberg, Cecilia

Published in:Gene Therapy

DOI:10.1038/sj.gt.3302430

2005

Link to publication

Citation for published version (APA):Lundberg, C. (2005). Stable, long-term label opens doors for gene therapy. Gene Therapy, 12(3), 195-195.https://doi.org/10.1038/sj.gt.3302430

Total number of authors:1

General rightsUnless other specific re-use rights are stated the following general rights apply:Copyright and moral rights for the publications made accessible in the public portal are retained by the authorsand/or other copyright owners and it is a condition of accessing publications that users recognise and abide by thelegal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private studyor research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal

Read more about Creative commons licenses: https://creativecommons.org/licenses/Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will removeaccess to the work immediately and investigate your claim.

Lentiviral vectors and stem cells...............................................................

Stable, long-term label opens doors forgene therapyC Lundberg. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Gene Therapy advance online publication, 2 December 2004; doi:10.1038/sj.gt.3302430

A new study shows that lentiviralvectors can be used to target andtransduce long-term repopulatingadult neural stem cells. This findingopens up the possibility of noveltherapeutic strategies for previouslyuntreatable diseases of the centralnervous system (CNS).

It was once generally thoughtthat the brain could not be mended.If broken it could never become thesame, just as a glass window cannever be put together again. SantiagoRamon y Cajal first articulated thisbelief early in the 20th century: ‘oncethe development was ended, thefounts of growth and regenerati-ony dried up irrevocably’.1 How-ever, at present it has been provenbeyond any doubt that new cellscontinue to be generated in the adultbrain: neurogenesis is clearly anongoing process.2 As early as the1960s, there were studies that indi-cated that new neurons were born inpostnatal life,3,4 but it is the recentrediscovery of this phenomenon thathas initiated the recent spate ofstudies that focus on this area.5,6

The potential therapeutic use ofadult neurogenesis offers hope tomany patient categories with neuro-logical diseases lacking effective cureat present. Now, in a paper in theProceedings of the National Acad-emy of Science USA, Consiglio et al7

show that they can transfer genes tothe stem cells in one of the neuro-genic zones of the brain, namely thesubventricular zone (SVZ).

Immature cells in the SVZ havebeen shown to differentiate into theneuronal cell types lost due to lesionssuch as stroke,8,9 but at very lownumbers. Neurogenesis in responseto such damage would need to beincreased in order to provide symp-tom relief in patients. Interestingly,an array of growth factors have beenshown to increase the proliferativeresponse and/or survival of the newborn cells,10 which clearly opens thedoor for gene therapy initiatives.

Using oncoretroviral-based vectors,a number of groups have labeledprecursors in the SVZ, but the veryfew of the slowly dividing neuralstem cells have been targeted.11–13

Consiglio et al7 now show that lenti-viral vectors, which transduce bothdividing and resting cells, can beused to label immature cells in theSVZ that generate neuronal progenyfor as long as 6 months. To furtherdemonstrate that the transduced cellsindeed represent a stem cell popula-tion, the authors applied an in vitroassay and proved that the GFP-positive cells had self-renewing capa-city and after clonal expansion couldgenerate differentiated cell types of allthree lineages in the brain – neurons,astrocytes and oligodendroglia.

The implications of these findingsare of different flavors. Firstly, theseresults imply that gene therapystrategies might be developed thatallow neurons lost through neurolo-gical disease or CNS damage to bereplaced: a very exciting prospect.Specifically lentiviral vectors couldbe used to encourage the stem cellsso that they participate more effec-tively on the healing process of thebrain and thus reduce symptoms ofdisease. The paper by Consiglio et al7

provides us with the first tool todo so effectively in the endogenousneural stem cell population. How-ever, are stem cells the ideal cell totarget? The effects of genes trans-ferred to stem cells will be inheritedto a large cohort of progeny for along period of time, possibly for life,and so the influence of this expand-ing population of transgenic cellsmight be hard to predict. Furtherstudies are needed to elucidate thisand will no doubt gain insight in theendogenous neural stem cell’s role innormal brain as well.

Secondly, there are implicationsfrom a more technical point of view.The use of lentiviral vectors mightcomplement the use of thymidineanalogs to label and study the

progeny of neural stem cells in thebrain especially after damage. Thevectors will label all progeny equallyand not be diluted in a pool of fastdividing cells, thus providing a moreaccurate representation of the fullproliferative response and its long-term consequences in the brain.Furthermore, lentiviral vectors couldbe used to create chimeras withspecific genetic modifications in theneural stem cell pool, which mightbe very helpful in uncovering theregulation of the neural stem cellsand their differentiation in intact anddamaged brain. In this context one ofthe strengths of lentiviral vectors –the ability to transduce nondividingas well as dividing cells – is also oneof their limitations. This abilitymeans that it is likely that at leastsome postmitotic neurons are mod-ified as well. This might not bea problem if the progeny that willbe studied migrate far away fromthe injection site as in the paper byConsiglio et al. However, this possi-bility should certainly be taken intoaccount if one needs to study neuro-genesis at sites closer to the injectionsite, such as the striatum, which laysadjacent to the SVZ. Further devel-opment of the targeting of the vectoritself might provide solutions to thislimitation. ’

C Lundberg is Associate Professor at theWallenberg Neuroscience Center, Departmentof Physiological Sciences, Lund University,BMC A11, 221 84 Lund, Sweden.E-mail: Cecilia.Lundberg@mphy.lu.se

1 Ramon y Cajal S. Degeneration andRegeneration of the Nervous System. Ox-ford University Press: Oxford, 1991.

2 Gage F. Science 2000; 287: 1433–1438.3 Altman J. J Comp Neurol 1969; 137:

433–457.4 Altman J, Das GD. J Comp Neurol 1965;

124: 319–335.5 Gould E, Gross CG. J Neurosci 2002; 22:

619–623.6 Kaplan MS. Trends Neurosci 2001; 24:

617–620.7 Consiglio A et al. Proc Natl Acad Sci USA

2004; 101: 14835–14840.8 Arvidsson A et al. Nat Med 2002; 8:

963–970.9 Parent JM et al. Ann Neurol 2002; 52:

802–813.10 Kokaia Z, Lindvall O. Curr Opin Neuro-

biol 2003; 13: 127–132.11 Falk A et al. Exp Cell Res 2002; 279: 34–39.12 Goldman JE. J Neurooncol 1995; 24: 61–64.13 Rogelius N, Ericson C, Lundberg C.

J Neurosci Methods (in press).

Gene Therapy (2004), 1& 2004 Nature Publishing Group All rights reserved 0969-7128/04 $30.00

www.nature.com/gt

NEWS AND COMMENTARY