Identification of targets and delivery platforms for gene therapy of neurodegenerative disorders is a clinical challenge. We describe a novel paradigm in which the neuroprotective gene is the herpes simplex virus type 2 (HSV-2) antiapoptotic gene ICP10PK and the vector is the growth-compromised HSV-2 mutant DeltaRR. DeltaRR is delivered intranasally. It is not toxic in rats and mice. ICP10PK is expressed in the hippocampus of the DeltaRR-treated animals for at least 42 days in the absence of virus replication and late virus gene expression. Its expression is regulated by an AP-1 amplification loop. Intranasally delivered DeltaRR prevents kainic acid-induced seizures, neuronal loss, and inflammation, in both rats and mice. The data suggest that DeltaRR is a promising therapeutic platform for neurodegenerative diseases.

Excessive glutamate receptor activation results in neuronal death, a process known as excitotoxicity. Intrastriatal injection of N-methyl-D-aspartate (NMDA) is a model of excitotoxicity. We used this model to examine whether excitotoxic injury is inhibited by the anti-apoptotic herpes simplex virus type 2 (HSV-2) protein, ICP10PK, delivered by the replication incompetent HSV-2 vector, ΔRR. Intrastriatal ΔRR administration (2500 plaque forming units) was nontoxic and did not induce microglial activation five days after injection. Intrastriatal injection of ΔRR with NMDA or four hours after NMDA injection showed increased neuronal survival and decreased mitochondrial damage compared to injection of NMDA alone. Neuroprotection was due to the inhibition of NMDAinduced apoptosis through ERK activation. ΔRR treated mice did not develop NMDA-associated behavioral deficits. The data suggests that ΔRR is a promising platform for treatment of acute neuronal injury.

We have previously shown that intrastriatal injection of Delta RR, the growth-compromised herpes simplex virus type 2 (HSV-2) vector for the antiapoptotic protein ICP10PK, prevents apoptosis caused by the excitotoxin N-methyl-D-aspartate (NMDA) in a mouse model of glutamatergic neuronal cell death (Golembewski et al. [2007] Exp. Neurol. 203:381-393). Because apoptosis regulation is stimulus and cell type specific, our studies were designed to examine the mechanism of Delta RR-mediated neuroprotection in striatal neurons. Organotypic striatal cultures (OSC) that retain much of the synaptic circuitry of the intact striatum were infected with Delta RR or a growth-compromised HSV-2 vector that lacks ICP10PK (Delta PK) and examined for neuroprotection-associated signaling. The mutated ICP10 proteins (p175 and p95) were expressed in 70-80% of neurons from Delta RR- and Delta PK-infected cultures, respectively, as determined by double-immunofluorescent staining with antibodies to ICP10 and NeuN or GAD65. Delta RR- but not Delta PK-treated OSC were protected from NMDA-induced apoptosis, as verified by ethidium homodimer staining, TUNEL, caspase-3 activation, and poly(AD-ribose) polymerase (PARP) cleavage. Neuroprotection was through ICP10PK-mediated activation of the survival pathways MEK/ERK and PI3-K/Akt, up-regulation of the antiapoptotic proteins Bag-1 and Bcl-2, and phosphorylation (inactivation) of the proapoptotic protein Bad. It was blocked by the MEK inhibitor U0126 or the PI3-K inhibitor LY294002, suggesting that either pathway can prevent NMDA-induced apoptosis. The data indicate that Delta RR-delivered ICP10PK stimulates redundant survival pathways that override proapoptotic cascades. Delta RR is a promising gene therapy platform against glutamatergic cell death.

Amid increasing demands from students and the public, universities have recently reinvigorated their efforts to increase the number of faculty from underrepresented populations. Although a myriad of piecemeal programs targeting individual recruitment and development have been piloted at several institutions, overall growth in faculty diversity remains almost negligible and highly localized. To bring about genuine change, we hypothesize a consortia approach that links individuals to hiring opportunities within a state university system might be more effective. Here we present a case study describing the progress of the NSF-funded Alliances for Graduate Education and the Professoriate (AGEP) PROMISE Academy Alliance, a consortium within the University System of Maryland (USM) collaborating to develop, implement, self-study, evaluate, and disseminate a unique postdoc-to-faculty conversion model in the biomedical sciences. The initiative centers on diversifying faculty across five institutions in the USM, including teaching-focused institutions, comprehensive universities, research institutions, and professional schools. Components of this approach include (1) enhanced recruiting and hiring practices to attract outstanding postdoctoral scholars from underrepresented backgrounds, (2) multi-institutional networking and professional development, and (3) facilitated processes to transition (or “convert”) postdocs into tenure-track positions at their postdoctoral institution or another institution in the state system. This model is distinct from more deficit-based approaches because it goes beyond focusing on building the individual’s skills to enter the professoriate. This program restructures the traditionally short-term nature of postdoctoral employment and incorporates a pathway to a tenure-track professorship at the same institution or within the same statewide system where the postdoc is trained. This multi-institutional model leverages collaboration and distinct institutional strengths to create cross-institutional support, advocacy, and policy. Importantly, it uses a decentralized financial structure that makes this approach distinctly replicable. Recognizing the immediate need for more collaborative approaches to diversify faculty and a lack of literature about such approaches, this case study describes the development of, and potential benefits of, a state university system, as well as the qualitative lessons learned from self-study, internal evaluation, external evaluation, and NSF site visits. The AGEP PROMISE Academy can serve as a model for replication at other university systems hoping to diversify their faculty.