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Summary:

Based upon the Research Committee's recommendation, the PGC Board decided to fund a proposal submitted by Dr. Judith Fridovich-Keil of Emory University. The Title of Dr. Fridovich-Keil's proposal is: Toward Improved Intervention for Galactosemia

The PGC Research Committee congratulates Dr. Fridovich-Keil and looks forward to hearing about the results of her study. A summary of the committee's work and Dr. Fridovich-Keil's proposal is provided below:

PGC Research Committee Members:

Therese Cozzo, Chair
Christy Johnson
Dan Lambert
Jo Beth Southard

Contact us at research@galactosemia.org

Background:

In 2005, PGC established a Research Fund specifically for the purpose of funding research into galactosemia. In parallel with the establishment of this new Research Fund, PGC also established a Research Committee whose purpose was to make recommendations to the PGC Board on how the funds from this research account would best be spent. During 2006 and 2007, the Research Committee designed a PGC Research Grants Program under which PGC could request proposals from researchers and professionals from around the world. (Research Grants Program documents describing the protocols for soliciting and reviewing proposals can be found here.) In order to support the proposal review by laypersons on the Research Committee and on PGC's Board, the committee also sought out professionals in the medical community to serve as volunteer peer reviewers to help evaluate the scientific merit of proposals.

First PGC Research Grants Program Call for Proposals:

On September 14, 2007, researchers and professionals were invited to submit research proposals for direct grant funding. The due date for proposals was October 12, 2007. Proposals that complied with the Research Grants Program policies were forwarded to volunteer peer reviewers. The research committee then used the results of the peer review process together with its own scoring rubric to evaluate each proposal.

In December 2007, the Research Committee shared the proposal evaluation results and funding recommendations with the PGC Board. In January 2008, the PGC Board notified the Research Committee of its decision on funding.

Results of the 2007 Research Grants Program:

Based upon the Research Committee's recommendation, the PGC Board decided to fund a proposal submitted by Dr. Judith Fridovich-Keil of Emory University.

The Title of Dr. Fridovich-Keil's proposal is: Toward Improved Intervention for Galactosemia

The PGC Research Committee congratulates Dr. Fridovich-Keil and looks forward to hearing about the results of her study.

The summary provided by Dr. Fridovich-Keil in her proposal is provided below:

Summary - Toward Improved Intervention for Galactosemia

Goals of the proposed work: The goal of the proposed work is to develop a strategy of supplemental intervention to minimize or prevent long-term complications in patients with classic galactosemia. The short-term goal of the proposed work is to identify and characterize a potent, specific, and bioactive small molecule inhibitor of human galactokinase (hGALK). Toward that end we propose to optimize and apply an existing simple, quantitative high throughput assay to screen appropriate chemical libraries for candidate hGALK inhibitors.

Motivation and rationale for the proposed work: Despite neonatal or even prenatal diagnosis and life-long dietary restriction of galactose, many if not most patients with classic galactosemia grow up to experience serious long-term complications. These complications include primary or premature ovarian failure in at least 80-90% of women, and cognitive and/or speech difficulties in close to half of all patients. Other complications, including ataxia, are also common. Unfortunately, despite many decades of research and clinical study, while the tools available for diagnosis and perhaps prognosis of galactosemia have improved, options for treatment have remained virtually unchanged. This is unacceptable. The rationale for this project stems from observations made in patients, mammalian cells, and yeast, all of which implicate an essential role for galactokinase as a mediator of galactose toxicity in galactosemia. We believe that an appropriately potent, specific, and bioactive small molecule inhibitor of human galactokinase could be administered as an oral medication to supplement dietary restriction of galactose in order to prevent or minimize the long-term complications otherwise experienced by so many patients with classic galactosemia.

Summary of the work proposed: We propose a two-part strategy to identify and characterize candidate small molecule inhibitors of human galactokinase. As a pilot, we will first screen a set of ~1000 small molecules predicted to be possible hGALK inhibitors via a computer screen of a large chemical library made publicly available by the National Cancer Institute (NCI). We will also screen the Spectrum Collection, a library of 2000 biologically active and structurally diverse small molecules available in our department. Of note, the Spectrum Collection contains the majority of current FDA approved drugs, all of which have been studied extensively in biological systems, and many of which have been found in screens, such as the one we propose, to have secondary, often unanticipated activities. We will apply appropriate secondary assays to evaluate any "positives" identified. Next, we will screen a larger library of >100,000 structurally diverse, chemically favorable compounds available to us through the Emory Chemistry-Biology Center for Discovery (CBCD). For access to additional libraries and relevant resources, especially structurally- directed libraries, we will also apply to the NIH Molecular Libraries Screening Center Network (MLSCN). As we identify small molecule hGALK inhibitors via these approaches, we will apply secondary assays to confirm the specificity, potency, bioactivity, and potential toxicity of the most promising candidates.

Future Goals: The proposed work represents a first small step in the long process of drug discovery, development, and application. But, we have to start somewhere.