Biology subjects

Lefcort, F.

Publications and source records attributed to Lefcort, F..

4 recordsLinked to original sources

bioRxiv2026

ELP1 Gene Augmentation Restores Visual Function in a Mouse Model of Familial Dysautonomia

Familial dysautonomia (FD) is an autosomal recessive sensory and autonomic neurodevelopmental and degenerative disorder characterized by complex neurological phenotypes. One of its most debilitating features is progressive optic neuropathy, which leads to severe visual impairment in FD patients by the third decade of life. Although several preclinical approaches have shown partial rescue of retinal ganglion cell (RGC) degeneration through increasing Elongator acetyltransferase complex subunit 1 (ELP1) expression in the retina, currently no treatments exist to prevent vision loss in FD. In this study, we performed a comprehensive analysis of visual function in a retina-specific FD mouse model (Pax6-Cre;Elp1loxp/loxp) and evaluated a gene supplementation strategy to restore human ELP1 protein levels in the retina. Longitudinal retinal assessments indicated that FD mice exhibit significant retinal nerve fiber layer (RNFL) thinning, as observed in FD patients. FD mice also showed reduced flash visual evoked potentials (VEPs), pattern electroretinography (pERGs), and photopic negative responses (phNRs) amplitudes, along with impaired visual acuity and contrast sensitivity, as assessed using optomotor response assay (OMR). Full-field electroretinography (ffERG) revealed reduced amplitude of dark-adapted a-waves, dark and light-adapted b-waves, indicating combined RGC and bipolar cell dysfunction. Intravitreal delivery of an adeno associated vector (AAV) vector (AAV2.U1a.hELP1) effectively restored physiological ELP1 protein expression, which resulted in a significant rescue of retinal structure and function. Gene supplementation with AAV2.U1a.hELP1 resulted in broad functional and structural improvement compared with untreated FD mice. In summary, our findings provide the first demonstration that ELP1 gene supplementation can effectively rescue RGC function in an FD mouse model and support AAV2.hELP1 at an optimized dose (5.4x108 vg) as a promising therapeutic approach for FD-associated optic neuropathy.

genetics↗

bioRxiv2023

Reduction of retinal ganglion cell death in mouse models of familial dysautonomia using AAV-mediated gene therapy and splicing modulators

Familial dysautonomia (FD) is a rare neurodevelopmental and neurodegenerative disease caused by a splicing mutation in the Elongator Acetyltransferase Complex Subunit 1 (ELP1) gene. The reduction in ELP1 mRNA and protein leads to the death of retinal ganglion cells (RGCs) and visual impairment in all FD patients. Currently, patient symptoms are managed, but there is no treatment for the disease. We sought to test the hypothesis that restoring levels of Elp1 would thwart the death of RGCs in FD. To this end, we tested the effectiveness of two therapeutic strategies for rescuing RGCs. Here we provide proof-of-concept data that gene replacement therapy and small molecule splicing modifiers effectively reduce the death of RGCs in mouse models for FD and provide pre-clinical data foundation for translation to FD patients.

neuroscience↗

bioRxiv2022

Elp1 is required for development of visceral sensory peripheral and central circuitry

Cardiovascular instability and a blunted respiratory drive in hypoxic conditions, are hallmark features of the genetic sensory and autonomic neuropathy, familial dysautonomia (FD). FD results from a mutation in the gene ELP1, whose encoded protein is a scaffolding subunit of the six subunit Elongator complex. In mice, we and others have shown that Elp1 is essential for the normal development of neural crest derived-dorsal root ganglia (DRG) sensory neurons. Whether Elp1 is also required for development of ectodermal placode-derived visceral sensory receptors which are required for normal baroreception and chemosensory responses, has not been investigated. Using mouse models for FD, our data indicate that in fact the entire circuitry underlying baroreception and chemoreception is impaired due to a requirement for Elp1 not only in the visceral sensory neuron ganglia, but also for normal peripheral target innervation, and in their CNS synaptic partners in the medulla. Thus Elp1 is required in both placode- and neural crest-derived sensory neurons and its reduction aborts the normal development of neuronal circuitry essential for autonomic homeostasis and interoception. Summary statementDue to faulty afferent sensory signaling, patients with Familial dysautonomia (FD) have a diminished sensory arm of the baroreflex which would normally modulate blood pressure, and they have a blunted response to hypoxia and hypercapnia (Norcliffe-Kaufmann et al. 2010). Using mouse models for FD, we reveal here the underlying pathology which may underlie these severely impaired homeostatic reflex pathways in FD.

neuroscience↗

bioRxiv2021

Loss of Elp1 disrupts trigeminal ganglion neurodevelopment in a model of Familial Dysautonomia

Familial Dysautonomia (FD) is a sensory and autonomic neuropathy caused by a mutation in Elongator complex protein 1 (ELP1). FD patients have small trigeminal nerves and impaired perception of facial pain and temperature. These signals are relayed by nociceptive neurons in the trigeminal ganglion, a structure comprised of both neural crest- and placode-derived cells. Mice lacking Elp1 in neural crest derivatives ("Elp1 CKO") are born with smaller trigeminal ganglia, suggesting Elp1 is important for trigeminal ganglion development, yet the function of Elp1 in this context is unknown. We demonstrate Elp1 expression in both neural crest- and placode-derived trigeminal neurons, which our data suggest give rise to primarily TrkA- and TrkB/C-expressing neurons, respectively. While Elp1 is not required for initial trigeminal ganglion formation, Elp1 CKO trigeminal neurons exhibit abnormal axon outgrowth and decreased target innervation. Developing nociceptors that express the receptor TrkA are especially vulnerable to Elp1 loss. TrkA expression is decreased in Elp1 CKO trigeminal nerve endings, coinciding with increased cell death. Subsequently, fewer TrkA neurons are present in the Elp1 CKO trigeminal ganglion, indicating Elp1 supports the target innervation and survival of trigeminal nociceptors. These findings explain the loss of facial pain and temperature sensation in FD.

developmental biology↗