Selected Grantee Publications
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- 8 results found
- Rare Diseases
- Women's Health
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Impaired Axon Initial Segment Structure and Function in a Model of ARHGEF9 Developmental and Epileptic Encephalopathy
Wang et al., PNAS. 2024.
https://www.pnas.org/doi/10.1073/pnas.2400709121
Researchers developed a mouse model carrying the G55A missense variant identified in ARHGEF9 patients with severe epilepsy and neurodevelopmental phenotypes. Using male Arhgef9G55A mice, this study examined behavioral, molecular, and electrophysiological phenotypes in the Arhgef9G55A model of developmental and epileptic encephalopathies (DEE). Researchers found that the G55A variant causes disruption of inhibitory postsynaptic organization and axon initial segment (AIS) architecture, leading to impairment of both synaptic transmission and action potential generation. The effects of Arhgef9G55A on neuronal function affect both intrinsic and synaptic excitability and preferentially impair AIS. These findings indicate a novel pathological mechanism of DEE and represent a unique example of a neuropathological condition converging from AIS dysfunctions. Supported by ORIP (U54OD020351, U54OD030187, U54OD020351, S10OD026974) and NINDS.
Placental Gene Therapy in Nonhuman Primates: A Pilot Study of Maternal, Placental, and Fetal Response to Non-Viral, Polymeric Nanoparticle Delivery of IGF1
Wilson et al., Molecular Human Reproduction. 2024.
https://academic.oup.com/molehr/article/30/11/gaae038/7876288#493719584
This study investigates a novel nanoparticle-mediated gene therapy approach for addressing fetal growth restriction (FGR) in pregnant female nonhuman primates. Using polymer-based nanoparticles delivering a human insulin-like growth factor 1 (IGF1) transgene, the therapy targets the placenta via ultrasound-guided injections. Researchers evaluated maternal, placental, and fetal responses by analyzing tissues, immunomodulatory proteins, and hormones (progesterone and estradiol). Findings highlight the potential of IGF1 nanoparticles to correct placental insufficiency by enhancing fetal growth, providing a groundbreaking advancement for in utero treatments. This research supports further exploration of nonviral gene therapies for improving pregnancy outcomes and combating FGR-related complications. Supported by ORIP (P51OD011106) and NICHD.
Amphiphilic Shuttle Peptide Delivers Base Editor Ribonucleoprotein to Correct the CFTR R553X Mutation in Well-Differentiated Airway Epithelial Cells
Kulhankova et al., Nucleic Acids Research. 2024.
https://academic.oup.com/nar/article/52/19/11911/7771564?login=true
Effective translational delivery strategies for base editing applications in pulmonary diseases remain a challenge because of epithelial cells lining the intrapulmonary airways. The researchers demonstrated that the endosomal leakage domain (ELD) plays a crucial role in gene editing ribonucleoprotein (RNP) delivery activity. A novel shuttle peptide, S237, was created by flanking the ELD with poly glycine-serine stretches. Primary airway epithelia with the cystic fibrosis transmembrane conductance regulator (CFTR) R533X mutation demonstrated restored CFTR function when treated with S237-dependent ABE8e-Cas9-NG RNP. S237 outperformed the S10 shuttle peptide at Cas9 RNP delivery in vitro and in vivo using primary human bronchial epithelial cells and transgenic green fluorescent protein neonatal pigs. This study highlights the efficacy of S237 peptide–mediated RNP delivery and its potential as a therapeutic tool for the treatment of cystic fibrosis. Supported by ORIP (U42OD027090, U42OD026635), NCATS, NHGRI, NHLBI, NIAID, NIDDK, and NIGMS.
Human Stem Cell-Derived Cardiomyocytes Integrate Into the Heart of Monkeys With Right Ventricular Pressure Overload
Scholz et al., Cell Transplantation. 2024.
https://journals.sagepub.com/doi/10.1177/09636897241290367
Patients with single-ventricle congenital heart defects suffer from right ventricular pressure overload (RVPO). Researchers developed a novel pulmonary artery banding (PAB) rhesus macaque model to induce RVPO. This study investigated the efficacy of human induced pluripotent stem cell cardiac lineage cell (hiPSC-CL) delivery at low or high dose into adult male and female rhesus macaques with right ventricular dysfunction. The findings indicate that hiPSC-CLs were successfully grafted and integrated to match the surrounding host right ventricle myocardium. These results suggest hiPSC-CL therapy is a potential adjunctive treatment for RVPO, but future research will be needed to elucidate the beneficial effects. Supported by ORIP (P51OD011106).
Intrinsic Link Between PGRN and GBA1 D409V Mutation Dosage in Potentiating Gaucher Disease
Lin et al., Human Molecular Genetics. 2024.
https://doi.org/10.1093/hmg/ddae113
Gaucher disease (GD) is an autosomal recessive disorder and one of the most common lysosomal storage diseases. GD is caused by mutations in the GBA1 gene that encodes glucocerebrosidase (GCase), a lysosomal protein involved in glyocolipid metabolism. Progranulin (PGRN, encoded by GRN) is a modifier of GCase, and GRN mutant mice exhibit a GD-like phenotype. The researchers in this study aimed to understand the relationship between GCase and PGRN. They generated a panel of mice with various doses of the GBA1 D409V mutation in the GRN-/- background and characterized the animals’ disease progression using biochemical, pathological, transcriptomic, and neurobehavioral analyses. Homozygous (GRN-/-, GBA1 D409V/D409V) and hemizygous (GRN-/-, GBA1 D409V/null) animals exhibited profound inflammation and neurodegeneration compared to PG96 wild-type mice. Compared to homozygous mice, hemizygous mice showed more profound phenotypes (e.g., earlier onset, increased tissue fibrosis, shorter life span). These findings offer insights into GD pathogenesis and indicate that GD severity is affected by GBA1 D409V dosage and the presence of PGRN. Supported by ORIP (R21OD033660) and NINDS.
De Novo Variants in FRYL Are Associated With Developmental Delay, Intellectual Disability, and Dysmorphic Features
Pan et al., The American Journal of Human Genetics. 2024.
https://www.cell.com/ajhg/fulltext/S0002-9297(24)00039-9
FRY-like transcription coactivator (FRYL) belongs to a Furry protein family that is evolutionarily conserved from yeast to humans, and its functions in mammals are largely unknown. Investigators report 13 individuals who have de novo heterozygous variants in FRYL and one individual with a heterozygous FRYL variant that is not confirmed to be de novo. The individuals present with developmental delay; intellectual disability; dysmorphic features; and other congenital anomalies in cardiovascular, skeletal, gastrointestinal, renal, and urogenital systems. Using fruit flies, investigators provide evidence that haploinsufficiency in FRYL likely underlies a disorder in humans with developmental and neurological symptoms. Supported by ORIP (U54OD030165), NHLBI, NICHD, and NCATS.
Association of Age at Menopause and Hormone Therapy Use With Tau and β-Amyloid Positron Emission Tomography
Coughlan et al., JAMA Neurology. 2023.
https://pubmed.ncbi.nlm.nih.gov/37010830/
To understand the predominance (70%) of women among individuals with Alzheimer’s disease, the investigators studied regional tau and β-amyloid (Aβ) in relation to age at menopause and hormone therapy (HT) in postmenopausal women and age-matched men using positron emission tomography. The study demonstrated that females exhibited higher tau deposition compared with age-matched males, particularly in the setting of elevated Aβ; earlier age at menopause and late initiation of HT were associated with increased tau vulnerability. This study suggests female individuals with these conditions may be at higher risk of pathological burden. Supported by ORIP (S10OD025245), NIA, and NICHD.
Effects of Early Daily Alcohol Exposure on Placental Function and Fetal Growth in a Rhesus Macaque Model
Lo et al., American Journal of Obstetrics and Gynecology. 2021.
https://www.sciencedirect.com/science/article/pii/S0002937821008309?via%3Dihub=
In a rhesus macaque model for chronic prenatal alcohol exposure, daily consumption during early pregnancy significantly diminished placental perfusion at mid to late gestation and significantly decreased the oxygen supply to the fetal vasculature throughout pregnancy. These findings were associated with the presence of microscopic placental infarctions. Although placental adaptations may compensate for early environmental perturbations to fetal growth, placental blood flow and oxygenation were reduced, consistent with the evidence of placental ischemic injury that persisted throughout pregnancy. Supported by ORIP (P51OD011092), NICHD, and NIAAA.