Dose-dependent treatment of optic nerve crush by exogenous systemic mutant erythropoietin.

The goal of the present study was to determine the minimum concentration of systemic erythropoietin-R76E required for neuroprotection in the retina. Erythropoietin (EPO) exhibits neuroprotective effects in both in vitro and in vivo models of neuronal cell death although its classical function is the regulation of red blood cell production. It can cross the blood brain barrier and therefore can be delivered systemically to affect the retina. However, long-term treatment with exogenous erythropoietin causes polycythemia. To decrease this potentially lethal effect, we generated and tested a modified form that contains a single arginine to glutamate mutation at the 76th position (EPO-R76E). In previous studies, this mutant protected retinal neurons in mouse models of retinal degeneration and glaucoma with similar efficacy as wild-type EPO. However, EPO-R76E has attenuated erythropoietic activity, therefore, neuroprotection can be achieved without causing a significant rise in hematocrit. BALB/cByJ mice received a single intramuscular injection of recombinant adeno-associated virus carrying enhanced green fluorescent protein, Epo, or Epo-R76E. To result in continuous production of four different doses of EPO-R76E, two doses of two different serotypes (2/5 and 2/8) were used. Mice were subjected to optic nerve crush and analysis was performed thirty days later. EPO-R76E showed dose-dependent protection of the retinal ganglion cell bodies, but was unable to prevent axonal degeneration. Furthermore, EPO-R76E induced a dose-dependent rise in the hematocrit that was still attenuated as compared to wild-type EPO.

Systemic adeno-associated virus-mediated gene therapy preserves retinal ganglion cells and visual function in DBA/2J glaucomatous mice.

A slow progressive death of neurons is the hallmark of neurodegenerative diseases, such as glaucoma. A therapeutic candidate, erythropoietin (EPO), has shown promise in many models of these diseases; however, it also causes polycythemia, a potentially lethal side effect. We have developed a novel mutant form of EPO that is neuroprotective but no longer erythropoietic by altering a single amino acid (arginine to glutamate at position 76; R76E). We hypothesized that a single intramuscular injection of recombinant adeno-associated virus carrying EpoR76E (rAAV2/5.CMV.EpoR76E) would protect retinal ganglion cells in a mouse model of glaucoma without inducing polycythemia. This systemic treatment not only protected the retinal ganglion cell somata located within the retina; it also preserved axonal projections within the optic nerve, while maintaining the hematocrit within normal limits. The rescued retinal ganglion cells retained their visual function demonstrated by flash visual evoked potentials. To our knowledge, this is the first demonstration of a therapy that protects neurons from death and prevents loss of visual function from the slow neurodegenerative effects of glaucoma. Because of its broad range of cellular targets, EpoR76E is likely to be successful in treating other neurodegenerative diseases as well.

Chicago wilderness: a new force in urban conservation.

In 1996, a coalition of diverse and determined organizations launched a new initiative in the Chicago region. Our vision? Chicago Wilderness: a thriving mosaic of natural areas, connected by greenways and wildlife corridors, embedded in the nation's third largest metropolis. In this vision, the region's human communities reclaim a cultural tradition of protecting and restoring the globally outstanding natural communities that enrich our lives. Today, more than 170 organizations join forces to transform this vision into reality. A regional biodiversity recovery plan, the result of 3 years of assessment and planning by scientists, land managers, educators, and policy strategists, sets priorities and determines the lines of action for the coalition. This regional agenda stems from our vision and recovery goals for each ecological community; it encourages targeted research initiatives that focus on characterizing our native biological diversity and on analyzing elements critical to its recovery. Ultimately, though, the long-term survival of our natural wealth rests on the support from the public. Although the challenges to conservation educators and communicators are many, Chicago Wilderness allows us to work together in understanding our audiences, channeling our resources, and creating novel approaches to engage the widest public in our conservation efforts.