Biology Reference
In-Depth Information
6. MODE OF DELIVERY: RECOMBINANT FACTORS
Neurotrophic factors can be delivered to injured RGCs in various
ways, either into the vitreal chamber of the eye itself or by application to
the injured ON or to central target regions for subsequent retrograde trans-
port by viable projecting neurons. Factors can be injected as a recombinant
protein, via nonviral or viral vector-based delivery of an appropriate gene, or
by transplantation of cells expressing an appropriate neurotrophic factor.
In general, mature RGCs are less responsive to trophic factors and have
reduced intrinsic regenerative potential (
Goldberg et al., 2002; Shen,
Wiemelt, McMorris, & Barres, 1999
), nonetheless numerous studies have
shown that injections of recombinant trophic factors support the survival
of a proportion of adult RGCs after ON injury. These factors include
BDNF, NT-4/5, GDNF, CNTF, and IGF-1 (e.g.,
Cui, Yip, Zhao, So, &
Harvey, 2003; Kermer, Klocker, Labes, & Bahr, 2000; Kl¨cker, Braunling,
Isenmann, & B¨hr, 1997; Leibinger et al., 2009; Mansour-Robaey,
Clarke, Wang, Bray, & Aguayo, 1994; Mey & Thanos, 1993; Peinado-
Ramon, Salvador, Villegas-P´rez, & Vidal-Sanz, 1996; Weber,
Viswanathan, Ramanathan, & Harman, 2010; Wen, Tao, Li, & Sieving,
2012; Zhang et al., 2005; Zhi et al., 2005
). Designed agonists of
neurotrophic receptors, for example TrkB, expressed by RGCs also
enhance survival (
Hu, Cho, & Goldberg, 2010
). Cooperative effects of
neurotrophins and cytokines on injured RGCs have also been
documented (e.g.,
Jo, Wang, & Benowitz, 1999; Koeberle & Ball, 2002;
Logan, Ahmed, Baird, Gonzalez, & Berry, 2006; Meyer-Franke et al.,
1995; Shen et al., 1999; Yan, Wang, Matheson, & Urich, 1999
). The
protective effect of these intraocular injections is, however, temporary,
perhaps because of bolus delivery of the peptides results in downregulation
of cognate receptors (
Frank, 1997; Meyer-Franke et al., 1998; Pease et al.,
2000
) or upregulation of pathways that negatively regulate intracellular
signaling (
Hellstr
¨
m, Muhling, et al., 2011; Park et al., 2009
).
The impact of neurotrophic factors on RGC axonal regrowth depends
on the type of factor that is used. Thus, intravitreal injection of recombinant
(r) BDNF or NT-4/5 induces sprouting of RGC axons proximal to the ON
injury, both within the retina and perhaps in the nerve stump itself (
Cui
et al., 2003; Mansour-Robaey et al., 1994; Pernet & Di Polo, 2006;
Sawai, Clarke, Kittlerova, Bray, & Aguayo, 1996
; see also
Hu et al.,
2010
), whereas
intraocular CNTF injections promote long-distance
