1996 Research Awards Announced

The Research Foundation has funded 53 years of neuroscience research since its first award was made in 1983. The awards have been made possible through the generosity of the AANS Membership, foundations, corporations, and interested individuals since fundraising began in 1980.

The Scientific Advisory Committee of the Research Foundation reviewed 37 grant applications for 1996 awards. As the Committee often finds, more high caliber proposals were submitted than were funds available to support the applicants. The following individuals’ proposals were ranked the highest and their funding began as of July 1996.

1996 Research Fellowship Awardee

Guy M. McKhann II, MD University of Washington/Seattle Sponsors: Philip A. Schwartzkroin, MD and Damir Janigro, MD Chairman: H. Richard Winn, MD

Project Title: Regulation of Potassium and Extracellular Space by the Astrocytic Syncytium in Gliotic Hippocampus

Dr. McKhann reports that although glial scarring has long been associated with focal epilepsy, studies to date have failed to establish a pathophysiologic linkage. There is increasing evidence, however, that central nervous system astrocytes play an essential role in regulating extracellular ion homeostasis and extracellular space (ECS) size in response to neuronal activity.

He will study astrocytic regulation of the extracellular environment in the kainate rat model of chronic temporal lobe epilepsy and in human specimens from temporal lobe epilepsy resections. He will test the hypothesis that there is altered regulation of potassium and/or extracellular space (ECS) size by the astrocytic syncytium in gliotic hippocampus. In particular, he will use electrophysiologic and optical imaging techniques to investigate potassium homeostasis, gap junctional conductance, and ECS changes in response to neuronal activity in hippocampal slices from kainate treated rats and human surgical specimens from temporal lobe epilepsy resections. From the results, he hopes to be able to determine:

• Whether astrocytes from gliotic hippocampus differ from normal astrocytes in their expression of voltage-sensitive ion channels or degree of gap junction coupling.
• If altered astrocytic ion channel expression or gap junction coupling can account for epileptiform activity.
• Whether ECS modifications resulting from hippocampal volume decrease and neuronal loss contribute to epileptogenesis in chronic animal model and human epilepsy.

1996 Research Fellowship Awardee

Frank Feigenbaum, MD Georgetown University Medical Center Sponsor and Chairman: Robert L. Martuza, MD

Project Title: Transcriptional Targeting of Recombinant HSV for Treatment of Nestin Producing Brain Tumors

Dr. Feigenbaum’s project will focus on the development of a novel method of viral-mediated tumor therapy using transcriptional targeting of Herpes Simplex Virus (HSV) in order to achieve cell specific replication and cytotoxicity. Viral replication will be regulated by promoter/enhancer elements for the nestin gene.

The nestin gene encodes a Class VI intermediate filament abundantly expressed in neoplastic human tissue of neuroepithelial origin. Such an approach should provide improved cell specificity compared to prior HSV strategies as well as improved intra-neoplastic spread. The specific aims of this project will be:

• To construct an HSV recombinant whose replication will be under the regulatory control of the nestin promoter/enhancer sequence.
• To test cell type specificity of recombinant viral replication in tumor cells in vitro.
• To test viral cytopathic effect on normal neural cells in vitro.
• To test anti-tumoral efficacy in vivo.
• To test the safety of recombinant viral inoculation.

1996 Young Clinician Investigator Awardee

James Markert, MD University of Alabama/Birmingham Sponsor: Richard J. Whitley, MD Chairman: Richard Morawetz, MD

Project Title: Mutant Herpes Simplex Virus as a Vector for IL-12 Cytokine Gene Therapy of Glioma

Despite aggressive surgical therapy, radiotherapy, and chemotherapy, malignant gliomas remain nearly always fatal. The proposal is to utilize advances in molecular biology to develop a new approach to glioblastoma therapy utilizing genetically engineered herpes simplex virus.

Dr. Markert’s lab has been pursuing the use of viral therapy utilizing engineered HSV in various animal models including CNS and non-CNS malignancies. Gamma 1 34.5 mutants have emerged as promising candidate viruses for tumor therapy. Dr. Markert proposes to combine virus therapy with gene therapy to increase its efficacy.

The object of this proposal is to develop a novel HSV construct utilizing cytokine gene therapy to increase its tumoricidal effects. An aneurovirulent construct containing a mutation of the gamma 1 34.5 gene will be utilized as the parent virus. Then a cytokine gene will be inserted under the control of a promoter enhancer element that is responsive to doxycycline. The efficacy and safety of the engineered viral construct will then be examined in vitro and in vivo models to determine activities.

Cytokine genes are particularly appealing as candidates for tumor gene therapy because involvement of the immune system may obviate the need for 100% efficiency of tumor cell gene transfer. However, external control of their level of expression will increase the safety of this therapy.

Careful selection of the genes to be transferred will be important. Two strategies will be utilized:

• use of a cytokine gene, IL-12, with known antineoplastic effects to increase the number of tumor cells killed by the therapy; and
• use of externally-controlled promoter/enhancer elements to control of the level of expression of this gene and titrate its effects to maximize efficacy and minimize toxicity.

Corporate Sponsors Recognized

In addition to the generous support that the Foundation has received from neurosurgeons, corporate sponsors have also stepped forward to ensure a strong future for the specialty through their support of research. These corporations have set a new standard for industry leadership and the Executive Council gratefully acknowledges their support.

Ensure Your Place on the Foundation’s 1996 Donor Wall

By Robert G. Ojemann, MD Chairman, Executive Council
AANS Research Foundation

The Foundation’s new “Donor Wall,” displayed for the first time in Minneapolis, will once again make an appearance during the 1997 AANS Annual Meeting in Denver next April. You can reserve a spot for your name on this display by making a commitment to the 1996 Campaign today.

Gifts to the Campaign are placed in the Foundation’s endowment fund which is currently valued at over $3.5 million. Income from this fund is used to fund Young Clinician Investigator Awards and Research Fellowships. Your investment in these research awards should be viewed as an investment in your personal future as well as that of the specialty as a whole.

As we move toward the end of 1996 and you plan your charitable giving, I urge you to include the Foundation as one of your priorities. Although most supporters choose to send a check to the Foundation, keep in mind that your gift can be pledged, with a pledge payment schedule tailored to meet your needs. You also now have the option of making your gift using your Mastercard or Visa. Gifts of stock should also be considered as there are definite tax benefits.

You may wish to make your gift as a tribute or as a memorial to a loved one, a colleague, or perhaps a mentor. Honorees, or family members, are notified that you have made a generous tribute or memorial gift to the Foundation. Gift amounts are never mentioned.

Be assured that your gift will be used in the most cost-effective and efficient manner possible. Foundation fundraising costs in 1995 totaled just 7%, which compares very favorably to other non-profit organizations, as shown in the chart on this page.

Share in the sense of pride and commitment that comes from making an annual gift to the Foundation. Join me in making a gift to the Foundation, at the highest possible level, today. I look forward to seeing your name on the Foundation’s 1996 Donor Wall next April, in Denver.

Remember also that many of your patients and family members are interested in supporting neuroscientific research. In your discussions of philanthropic opportunities with these potential donors, please offer a copy of the Foundation’s “grateful patient” brochure, which you recently received in the mail. These brochures present a solid overview of the Foundation and are highly effective in soliciting additional support for research. Contact Joan Vaughn, Development Officer, at (847)692-9500 for extra copies of the brochure.

For your convenience, a Research Foundation gift envelope has been inserted in this issue of the AANS Bulletin.