Examining the therapeutic potential for gene replacement therapy in a mouse model of SLC35A2 deficiency

Active Project Grant Awarded Last action

Award ID
F31NS149631
Recipient
Awarding agency
Obligated
$38,911

Award facts

Assistance listing
93.853 Extramural Research Programs in the Neurosciences and Neurological Disorders
Completion date 0% complete
Place of performance
Columbus, OH 43205, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Epilepsy is one of the most common chronic neurological disorders and is characterized by recurrent, unprovoked seizures. While many medications are available to decrease the frequency and severity of these seizures, IT is estimated that one-third of these cases do not respond adequately to currently available medications. Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) is a newly defined histopathological entity characterized by the presence of heterotopic neurons, clusters of OLIG2-positive cells and its strong association with drug-resistant epilepsy. Somatic variants in the X-linked SLC35A2 gene that encodes a golgi-localized UDP-galactose transporter have been implicated as a prominent cause of MOGHE. Deficiency in SLC35A2 leads to alterations in the glycosylation profiles of various glycoproteins necessary for cell signaling and homeostasis. While surgical resection of the epileptic focus can be curative in many cases, IT cannot be performed when the area designated for resection coincides with a brain area of high functional importance. Therefore, there is a critical need for an alternative medical treatment for MOGHE. The major barrier to the development of new therapies is our lack of understanding of the mechanisms that lead to the development of histopathological phenotypes and seizures. Specifically, IT is unknown whether cortical malformations are a prerequisite for seizure onset or if seizures develop through an independent mechanism. In addition, IT is unknown whether these phenotypes occur due to cell-autonomous effects of variants in SLC35A2 or if contributions from multiple cell types are necessary. This proposal outlines a comprehensive research plan to address these questions by replacing the SLC35A2 gene in a mouse model of SLC35A2 deficiency using recombinant adeno-associated viral vectors (AAVS) at specific timepoints and in certain cell types. The central hypothesis is that gene replacement therapy will improve the phenotypic outcomes of mice deficient in SLC35A2 in a timing- and cell type-dependent manner. Aim 1 will examine the relationship between cortical malformations and epilepsy and whether they are inherently tied together or independent phenomena by varying the timing of gene replacement. Aim 2 examines the contributions of SLC35A2 deficiency in neurons and oligodendrocytes to the development of various histopathological phenotypes and seizures by isolating the gene replacement to specific cell types. If successful, the work will establish the F easibility of a novel treatment for these patients and further our understanding of the mechanisms that lead to disease, while providing the applicant a rigorous pre-doctoral training program in neurogenetics.

Quick answers

Who received award F31NS149631?

F31NS149631 was awarded to Research Institute At Nationwide Children's Hospital by National Institute of Neurological Disorders and Stroke (National Institutes of Health) on January 1, 2027.

How much is award F31NS149631 worth?

$38,911 has been obligated on F31NS149631.

On GovTribe

See this award's full record

  • Every transaction and subaward
  • The recipient's other awards and teaming partners
  • Similar grant awards
  • Ask GovTribe AI about this award
Try for free Login