Optimal window of opportunity for granulosa cell gene therapy in galactosemia
Ended Project Grant Awarded Last action
- Award ID
- R21HD113931
- Recipient
-
University Of Utah UEI LL8GLEVH6MG3
- Awarding agency
-
National Institute of Child Health and Human Development
National Institutes of Health, Department of Health and Human Services
- Obligated
- $425,071
Award facts
- Assistance listing
- 93.865 Child Health and Human Development Extramural Research
- Completion date
- Place of performance
- Emigration Canyon, UT 84108, USA
Award details come from USAspending.gov.
Description
- Abstract
- Hereditary deficiency of galactose-1-phosphate uridylyltransferase (galt, E.C. 2.7.7.12) activity in humans can lead to a potentially lethal disease called classic galactosemia (omim 230400). Despite the life-saving consequences of newborn screening, early diagnosis, and a galactose-restricted diet, affected women invariably show ovarian damage and fertility impairment representing the greatest burden of their disease. There are currently no satisfactory treatments available to prevent this complication. Recently, insights into the underlying pathophysiology and innovative technological advancements have become available, and options for curative treatment have emerged. Using this momentum, we aim to develop a treatment to prevent fertility impairments. We aim to 1) develop a non-viral nucleic acid therapy approach that targets the ovary and 2) determine the optimal timing to rescue the ovarian function. Folliculogenesis is driven by the cross-talk between oocytes and granulosa cells. Restoration of galt activity in these cells could possibly rescue the ovarian damage. In this pilot grant application, we will explore a new modality of gene therapy using nanoparticles encapsulating episomal galt cdna within a non-viral expression vector. This will include determination of the optimal cationic polymer layer for delivery of episomal DNA plasmids expressing GFP or galt to granulosa cell lines and the addition of ligands to encourage uptake and promote specificity. In addition, we will determine the optimal window of opportunity for this treatment. A prenatal origin has been considered for decades whereas the data currently available, albeit scarce, favor a postnatal origin. There is undoubtedly early damage, but whether treatments aimed to prevent ovarian damage needs to be started in the neonatal period, or treating in infancy or adolescence would suffice, is not clear. This will be studied using the zebrafish model for classic galactosemia that mimics the fertility impairments and is suitable for studies through development. Zebrafish reproduction is regulated by the brain-pituitary-gonadal axis, comparable to the human situation. For this purpose, RNA-SEQ, histology/immunohistochemistry of follicole development and single cell RNA-SEQ of oocytes and granulosa cells at 4 developmental stages will be studied. These studies will uncover developmental stage and cell-specific alterations in the affected ovaries. Distinctive patterns at the different stages are expected to reveal at which stage(S) damage can be prevented/halted using ovary targeted gene therapy.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $171,904 | |
| Original award | $253,167 |
Subawards
| Subrecipient | Amount | Awarded |
|---|---|---|
| Cleveland Clinic Lerner College Of Medicine Of Case Western Reserve University | $83,708 | |
| The Children's Hospital Corporation | $166,877 | |
| Universiteit Maastricht | $74,313 |
Quick answers
Who received award R21HD113931?
R21HD113931 was awarded to University Of Utah by National Institute of Child Health and Human Development (National Institutes of Health) on August 23, 2024.
How much is award R21HD113931 worth?
$425,071 has been obligated on R21HD113931.
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