RARE DISEASE
Familial dysautonomia
Familial dysautonomia
Familial dysautonomia
Synonyms: HSAN3, Hereditary sensory and autonomic neuropathy type 3, Hereditary sensory and autonomic neuropathy type III, Riley-Day syndrome
Synonyms: HSAN3, Hereditary sensory and autonomic neuropathy type 3, Hereditary sensory and autonomic neuropathy type III, Riley-Day syndrome
Synonyms: HSAN3, Hereditary sensory and autonomic neuropathy type 3, Hereditary sensory and autonomic neuropathy type III, Riley-Day syndrome
Drug discovery
3
drugs
With orphan designations
Overview
Familial dysautonomia (FD) is an autosomal recessive disorder caused by ELP1 gene mutations, leading to developmental deficits in autonomic and sensory neurons. It primarily affects Ashkenazi Jews (1:3,700 incidence). Core features include blood pressure lability, neurogenic dysphagia, recurrent aspiration pneumonia, temperature dysregulation, and progressive sensory/autonomic dysfunction. Diagnosis combines genetic testing with clinical signs (e.g., absent overflow tears, absent fungiform papillae) [1][2][11].
Burden
High morbidity: Recurrent pneumonia (54% of hospitalizations), renal impairment, fractures (63% prevalence), and progressive scoliosis [1][5][7]
Leading mortality causes: Respiratory failure (53% of deaths) and sudden unexpected death during sleep [5][11][16]
40% require assisted mobility by adulthood due to ataxia; 30% develop optic neuropathy [7][19]
Therapies
Blood pressure control: Fludrocortisone, midodrine, and benzodiazepines to stabilize autonomic crises [11][13][19]
Aspiration prevention: Gastrostomy, Nissen fundoplication, and thickened feeds [3][5][19]
Respiratory support: Airway clearance techniques, non-invasive ventilation for sleep-disordered breathing [5][19]
Categories: rare genetic diseases, rare neurological diseases, rare ophthalmic disorders, rare skin diseases
Research Papers
207 drug discovery papers about Familial dysautonomia, with 1 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
207 drug discovery papers about Familial dysautonomia, with 1 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2025-03-09 | Carbidopa: beyond Parkinson's disease.
To revisit the pharmacology and real-world use of carbidopa in the management of autonomic disorders. To identify articles suitable for this review, a search of the PubMed database was conducted in January 2025 using the keywords "Carbidopa," "MK-486," and "L-alpha-methyldopa hydrazine." The pharmacotherapeutic role of carbidopa extends beyond the management of Parkinson's disease. Our literature search revealed the use of carbidopa in three primary autonomic diseases to treat either nausea or symptoms of sympathetic hyperactivity: (1) familial dysautonomia, (2) hyperadrenergic postural orthostatic tachycardia syndrome (POTS), and (3) afferent baroreflex failure (familial or acquired). Even at a dose as high as 600 mg/day, carbidopa was not associated with bothersome side effects in some of the clinical trials on familial dysautonomia. Pre-clinical evidence also suggests in vitro and in vivo inhibition of T-cell activation by carbidopa and a potential therapeutic use in cytokine release syndrome. Current evidence, although limited, suggests that carbidopa has a favorable safety profile. While large, well-designed studies are warranted, observations from case series and small studies suggest that carbidopa could have utility in treating nausea in familial dysautonomia and symptoms of sympathetic hyperactivity in hyperadrenergic postural orthostatic tachycardia syndrome (POTS) and afferent baroreflex failure.
2024-11-28 | Laminin β4 is required for the development of human peripheral sensory neurons.
The extracellular matrix (ECM) is a mixture of glycoproteins and fibrous proteins that provide the biophysical properties necessary to maintain cellular homeostasis. ECM integrity is of particular importance during development, where it allows proper migration and cellular differentiation. Laminins are ECM heterotrimeric proteins consisting of α, β, and γ chains. There are five known α chains, four β chains, and three γ chains. Thus, there are 60 potential combinations for laminin trimers, however only 16 laminin trimers have been identified to date. Furthermore, none of them contain laminin β4 and its function is unknown. Here, we sought to characterize the role of LAMB4 (the gene encoding laminin β4) during human embryonic development of the peripheral sensory nervous system. Using human pluripotent stem cells (hPSCs), we found that LAMB4 is expressed in the ectoderm in the early stages of sensory neuron (SN) specification. SNs, part of the peripheral nervous system, are specialized neurons that detect pain, temperature, and touch. Surprisingly, more than 20 million people in the US have some form of peripheral nerve damage (including SNs), however there are very few treatment options available. Learning about the biology of peripheral neurons will uncover potential new therapeutic targets, thus we focused on understanding the effects of LAMB4 in SNs. First, we knocked out LAMB4 in hPSCs, using CRISPR/Cas9, and found that loss of LAMB4 impairs the migration of the SN progenitors neural crest cells (NCCs) and harms SN development and survival. To assess if LAMB4 has clinical relevance, we studied the genetic disorder Familial Dysautonomia (FD), which specifically affects the peripheral nervous system. FD is caused by a mutation in ELP1 (a component of the Elongator complex) leading to developmental and degenerative defects in SNs. A previous report showed that patients with severe FD harbor additional single nucleotide variants in LAMB4. We found that these variants sharply downregulate the expression of LAMB4 and laminin β4 levels in SNs differentiated from induced pluripotent stem cells (iPSCs) reprogramed from patients with severe FD. Moreover, a healthy ECM is sufficient to rescue the developmental phenotypes of FD, further confirming that ECM defects contribute significantly to the etiology of FD. Finally, we found that LAMB4/laminin β4 is necessary for actin filament accumulation and it interacts with laminin α4 and laminin γ3, forming the laminin-443, a previously unreported laminin trimer. Together, these results show that LAMB4 is a critical, but largely unknown gene required for SN development and survival.
2024-11-20 | Genipin rescues developmental and degenerative defects in familial dysautonomia models and accelerates axon regeneration.
The peripheral nervous system (PNS) is essential for proper body function. A high percentage of the world's population suffers from nerve degeneration or peripheral nerve damage. Despite this, there are major gaps in the knowledge of human PNS development and degeneration; therefore, there are no available treatments. Familial dysautonomia (FD) is a devastating disorder caused by a homozygous point mutation in the gene ELP1. FD specifically affects the development and causes degeneration of the PNS. We previously used patient-derived induced pluripotent stem cells (iPSCs) to show that peripheral sensory neurons (SNs) recapitulate the developmental and neurodegenerative defects observed in FD. Here, we conducted a chemical screen to identify compounds that rescue the SN differentiation inefficiency in FD. We identified that genipin restores neural crest and SN development in patient-derived iPSCs and in two mouse models of FD. Additionally, genipin prevented FD degeneration in SNs derived from patients with FD, suggesting that it could be used to ameliorate neurodegeneration. Moreover, genipin cross-linked the extracellular matrix (ECM), increased the stiffness of the ECM, reorganized the actin cytoskeleton, and promoted transcription of yes-associated protein-dependent genes. Last, genipin enhanced axon regeneration in healthy sensory and sympathetic neurons (part of the PNS) and in prefrontal cortical neurons (part of the central nervous system) in in vitro axotomy models. Our results suggest that genipin has the potential to treat FD-related neurodevelopmental and neurodegenerative phenotypes and to enhance neuronal regeneration of healthy neurons after injury. Moreover, this suggests that the ECM can be targeted to treat FD.
2024-09-04 | Neuronal and glial cell alterations involved in the retinal degeneration of the familial dysautonomia optic neuropathy.
Familial dysautonomia (FD) is a rare genetic neurodevelopmental and neurodegenerative disorder. In addition to the autonomic and peripheral sensory neuropathies that challenge patient survival, one of the most debilitating symptoms affecting patients' quality of life is progressive blindness resulting from the steady loss of retinal ganglion cells (RGCs). Within the FD community, there is a concerted effort to develop treatments to prevent the loss of RGCs. However, the mechanisms underlying the death of RGCs are not well understood. To study the mechanisms underlying RGC death, Pax6-cre;Elp1loxp/loxp male and female mice and postmortem retinal tissue from an FD patient were used to explore the neuronal and non-neuronal cellular pathology associated with the FD optic neuropathy. Neurons, astrocytes, microglia, Müller glia, and endothelial cells were investigated using a combination of histological analyses. We identified a novel disruption of cellular homeostasis and gliosis in the FD retina. Beginning shortly after birth and progressing with age, the FD retina is marked by astrogliosis and perturbations in microglia, which coincide with vascular remodeling. These changes begin before the onset of RGC death, suggesting alterations in the retinal neurovascular unit may contribute to and exacerbate RGC death. We reveal for the first time that the FD retina pathology includes reactive gliosis, increased microglial recruitment to the ganglion cell layer (GCL), disruptions in the deep and superficial vascular plexuses, and alterations in signaling pathways. These studies implicate the neurovascular unit as a disease-modifying target for therapeutic interventions in FD.
2024-06-13 | Marine alkaloid rigidin analogues as potential selective inhibitors of SHP1, a new strategy for cancer immunotherapeutics.
SHP1 is a protein tyrosine phosphatase playing a central role in immunity, cell growth, development, and survival. The inhibition of SHP1 can help in better prognosis in various disorders like breast and ovarian cancer, melanoma, atherosclerosis, hypoxia, hypoactive immune response, and familial dysautonomia. The currently available inhibitors of SHP1 have the side effect of inhibiting the activity of SHP2, which shares >60% sequence similarity with SHP1 but has distinct biological functions. Thus, there is a need to search for novel specific inhibitors of SHP1. The current study uses a combination of virtual screening and molecular dynamic simulations, followed by PCA and MM-GBSA analysis, to screen about 35000 compounds; to predict that two rigidin analogues can potentially selectively inhibit SHP1 but not SHP2. Our studies demonstrate that these rigidin analogues are more potent at inhibiting SHP1 than the commercially available inhibitor NSC-87877. Further, cross-binding studies with SHP2 exhibited poor binding efficiency and lower stability of the complex, thus indicating a specificity of the rigidin analogues for SHP1, which is crucial in preventing side effects due to the diverse physiological functions of SHP2 in cellular signaling, proliferation, and hematopoiesis. Additionally, SHP1 is essential in mediating the inhibitory signaling in antitumor immune cells like NK and T cells. Hence, the rigidin analogues that inhibit SHP1 will potentiate the anti-tumor immune response by the release of inhibitory function of NK cells, thus driving NK activating response, in addition to their intrinsic anti-tumor function. Thus, SHP1 inhibition is a novel double-blade approach towards anti-cancer immunotherapeutics.Communicated by Ramaswamy H. Sarma.
proteins
2024-01-22 | Linking the Extended Autonomic System with the Homeostat Theory: New Perspectives about Dysautonomias
Dysautonomias are conditions in which altered functions of one or more components of the autonomic nervous system (ANS) adversely affect health. This essay is about how elucidating mechanisms of dysautonomias may rationalize personalized treatments. Emphasized here are two relatively new ideas-the "extended" autonomic system (EAS) and the "homeostat" theory as applied to the pathophysiology and potential treatments of dysautonomias. The recently promulgated concept of the EAS updates Langley's ANS to include neuroendocrine, immune/inflammatory, and central components. The homeostat theory builds on Cannon's theory of homeostasis by proposing the existence of comparators (e.g., a thermostat, glucostat, carbistat, barostat) that receive information about regulated variables (e.g., core temperature, blood glucose, blood gases, delivery of blood to the brain). Homeostats sense discrepancies between the information and response algorithms. The presentation links the EAS with the homeostat theory to understand pathophysiological mechanisms of dysautonomias. Feed-forward anticipatory processes shift input-output curves and maintain plateau levels of regulated variables within different bounds of values-"allostasis". Sustained allostatic processes increase long-term wear-and-tear on effectors and organs-allostatic load. They decreaseing thresholds for destabilizing and potentially fatal positive feedback loops. The homeostat theory enables mathematical models that define stress, allostasis, and allostatic load. The present discussion applies the EAS and homeostat concepts to specific examples of pediatric, adolescent/adult, and geriatric dysautonomias-familial dysautonomia, chronic orthostatic intolerance, and Lewy body diseases. Computer modeling has the potential to take into account the complexity and dynamics of allostatic processes and may yield testable predictions about individualized treatments and outcomes.
2023-11-09 | Height, weight, and body mass index in patients with familial dysautonomia
Children with familial dysautonomia (FD) are smaller and grow more slowly than the general population. It is unknown whether this abnormal growth is due to comorbidities that patients with FD live with, or if it is a direct effect of the disease-causing homozygous ELP-1 mutations. Here, we created growth curves for weight, height, and body mass index (BMI) in male and female children with FD to monitor the nutritional status of patients with FD.We used the New York University (NYU) FD Registry which includes data from 680 individuals with FD who were followed longitudinally since birth. We generated sex-specific FD growth charts for three age ranges (birth to 36 months, 2 to 20 years, and 2 to 40 years) and compared them to the general population. We generated Kaplan-Meier curves to test the hypothesis that FD patients with low BMI had shorter survival than the rest of the cohort.Growth charts generated from 591 individuals with FD show that these patients grow more slowly, reach less height, and gain less weight than the general population. The impact of FD on height was more pronounced in girls than in boys. However, both groups showed markedly low weights, which resulted in low BMI. Low weight, but not height, is already evident at birth. In a subpopulation of FD patients, we found that treatment with growth hormone or spinal fusion surgery helped patients achieve the expected growth characteristic of FD patients, but these treatments did not lead FD patients to achieve the growth pattern of the general population. Contrary to our hypothesis, low BMI had no impact on patient survival.Pediatric patients with FD have lower height, weight, and BMI compared to the general pediatric population, but this does not appear to affect survival. Growth curves specific to the FD population are an important tool to monitor growth and nutritional status in pediatric patients with FD when the general population growth curves are of limited use.
2017-06-23 | Pathological Confirmation of Optic Neuropathy in Familial Dysautonomia.
Clinical data suggest that optic neuropathy and retinal ganglion cell loss are the main cause of visual decline in patients with familial dysautonomia, but this has not previously been confirmed by pathological analyses. We studied retinas and optic nerves in 6 eyes from 3 affected patients obtained at autopsy. Analyses included routine neurohistology and immunohistochemistry for neurofilaments, cytochrome c oxidase (COX), and melanopsin-containing ganglion cells. We observed profound axon loss in the temporal portions of optic nerves with relative preservation in the nasal portions; this correlated with clinical and optical coherence tomography findings in 1 patient. Retinal ganglion cell layers were markedly reduced in the central retina, whereas melanopsin-containing ganglion cells were relatively spared. COX staining was reduced in the temporal portions of the optic nerve indicating reduced mitochondrial density. Axonal swelling with degenerating lysosomes and mitochondria were observed by electron microscopy. These findings support the concept that there is a specific optic neuropathy and retinopathy in patients with familial dysautonomia similar to that seen in other optic neuropathies with mitochondrial dysfunction. This raises the possibility that defective expression of the IkB kinase complex-associated protein (IKAP) resulting from mutations in IKBKAP affects mitochondrial function in the metabolism-dependent retinal parvocellular ganglion cells in this condition.
2017-06-07 | RBM24 promotes U1 snRNP recognition of the mutated 5' splice site in the IKBKAP gene of familial dysautonomia.
The 5' splice site mutation (IVS20+6T>C) of the inhibitor of κ light polypeptide gene enhancer in B cells, kinase complex-associated protein (IKBKAP) gene in familial dysautonomia (FD) is at the sixth intronic nucleotide of the 5' splice site. It is known to weaken U1 snRNP recognition and result in an aberrantly spliced mRNA product in neuronal tissue, but normally spliced mRNA in other tissues. Aberrantly spliced IKBKAP mRNA abrogates IKK complex-associated protein (IKAP)/elongator protein 1 (ELP1) expression and results in a defect of neuronal cell development in FD. To elucidate the tissue-dependent regulatory mechanism, we screened an expression library of major RNA-binding proteins (RBPs) with our mammalian dual-color splicing reporter system and identified RBM24 as a regulator. RBM24 functioned as a cryptic intronic splicing enhancer binding to an element (IVS20+13-29) downstream from the intronic 5' splice site mutation in the IKBKAP gene and promoted U1 snRNP recognition only to the mutated 5' splice site (and not the wild-type 5' splice site). Our results show that tissue-specific expression of RBM24 can explain the neuron-specific aberrant splicing of IKBKAP exon 20 in familial dysautonomia, and that ectopic expression of RBM24 in neuronal tissue could be a novel therapeutic target of the disease.
2014-11-19 | Involvement of IKAP in Peripheral Target Innervation and in Specific JNK and NGF Signaling in Developing PNS Neurons
A splicing mutation in the ikbkap gene causes Familial Dysautonomia (FD), affecting the IKAP protein expression levels and proper development and function of the peripheral nervous system (PNS). Here we attempted to elucidate the role of IKAP in PNS development in the chick embryo and found that IKAP is required for proper axonal outgrowth, branching, and peripheral target innervation. Moreover, we demonstrate that IKAP colocalizes with activated JNK (pJNK), dynein, and β-tubulin at the axon terminals of dorsal root ganglia (DRG) neurons, and may be involved in transport of specific target derived signals required for transcription of JNK and NGF responsive genes in the nucleus. These results suggest the novel role of IKAP in neuronal transport and specific signaling mediated transcription, and provide, for the first time, the basis for a molecular mechanism behind the FD phenotype.
gene therapies
2026-04-11 | Prime editing of the common Familial Dysautonomia-causing c.2204 + 6T > C splicing mutation.
Familial Dysautonomia (FD, OMIM #223900) is a rare, life-threatening autosomal recessive neuropathy caused in 99.8% of patients by the c.2204 + 6T > C intronic mutation in the ELP1/IKAP gene. This substitution induces exon 20 skipping, leading to reduced ELP1 expression. While splicing-modulating therapies have shown partial efficacy, a permanent genetic correction remains unavailable. Here, we report the first application of Prime Editing (PE) to rescue the FD-causing IKAP splicing defect. Using a mutant exon-trapping minigene (pTB-IKAP) transiently co-transfected in HEK293T cells with PE2 or PE3 components, we demonstrate a significant increase in exon 20 inclusion, from 19 ± 2% to 48 ± 3% and 60 ± 3%, respectively. Restriction fragment length polymorphism and Sanger sequencing confirmed correction of the mutant allele, with PE3 achieving ~ 10% genomic editing efficiency. Moreover, by targeting ESS2 via a silent A > G substitution, we similarly restored exon inclusion to 50 ± 4%. These findings provide proof-of-principle that prime editing, particularly PE3, can efficiently correct or bypass the ELP1/IKAP c.2204 + 6T > C mutation and restore proper splicing. Given that modest increases in ELP1 expression (5-10% of wild-type) markedly alleviate FD severity in mouse models, our results highlight PE as a promising, potentially curative approach and lay the foundation for future ex-vivo and in vivo studies.
2026-04-10 | Prime editing of the common Familial Dysautonomia-causing c.2204 + 6T > C splicing mutation
Abstract Familial Dysautonomia (FD, OMIM #223900) is a rare, life-threatening autosomal recessive neuropathy caused in 99.8% of patients by the c.2204 + 6T > C intronic mutation in the ELP1/IKAP gene. This substitution induces exon 20 skipping, leading to reduced ELP1 expression. While splicing-modulating therapies have shown partial efficacy, a permanent genetic correction remains unavailable. Here, we report the first application of Prime Editing (PE) to rescue the FD-causing IKAP splicing defect. Using a mutant exon-trapping minigene (pTB-IKAP) transiently co-transfected in HEK293T cells with PE2 or PE3 components, we demonstrate a significant increase in exon 20 inclusion, from 19 ± 2% to 48 ± 3% and 60 ± 3%, respectively. Restriction fragment length polymorphism and Sanger sequencing confirmed correction of the mutant allele, with PE3 achieving ~ 10% genomic editing efficiency. Moreover, by targeting ESS2 via a silent A > G substitution, we similarly restored exon inclusion to 50 ± 4%. These findings provide proof-of-principle that prime editing, particularly PE3, can efficiently correct or bypass the ELP1/IKAP c.2204 + 6T > C mutation and restore proper splicing. Given that modest increases in ELP1 expression (5–10% of wild-type) markedly alleviate FD severity in mouse models, our results highlight PE as a promising, potentially curative approach and lay the foundation for future ex-vivo and in vivo studies.
2026-01-16 | 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 ⁺ ;Elp1 loxp/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 (5.4×10 8 vg) as a promising therapeutic approach for FD-associated optic neuropathy.
2025-10-03 | Peripheral neuron phenotypes of familial dysautonomia are rescued by AAV-mediated gene therapy.
Familial dysautonomia (FD) is a rare genetic, neurodevelopmental and neurodegenerative disorder, where a homozygous mutation in the ELP1 gene is responsible for defects and symptoms found in 99% of patients (1). FD symptoms mainly affect the peripheral nervous system (PNS) (2), including the autonomic and sensory nervous systems (ANS, SNS) (3). The ANS regulates unconscious physiological responses and maintains body homeostasis, such as heart rate, blood pressure, gland secretion, and breathing, which are vital for bodily function. The SNS is the key mediator that processes and relays sensory information from the internal and external environment to the brain, including limb position, temperature, and pain.
2025-09-02 | AAV2-mediated intravitreal delivery of exon-specific U1 snRNA rescues optic neuropathy in a mouse model of familial dysautonomia.
Familial dysautonomia (FD) is a rare autosomal recessive neurodegenerative disorder caused by a splicing mutation in the ELP1 gene. It predominantly affects the sensory and autonomic nervous systems, with progressive vision loss due to optic neuropathy being a universal and debilitating symptom. Retinal pathology in FD involves progressive thinning of the retinal nerve fiber layer (RNFL), resulting from the degeneration of retinal ganglion cells (RGCs). Notably, FD-associated vision loss has a postnatal onset, offering a critical window for therapeutic intervention before severe visual impairment develops in adolescence. Currently, no approved treatments exist to prevent or reverse vision loss in FD. In this study, we present a novel RNA-based therapeutic approach targeting ELP1 pre-mRNA splicing in the retina. We engineered exon-specific U1 small nuclear RNAs (ExSpeU1s) to enhance inclusion of exon 20 in the mutant ELP1 transcripts in the retina, thereby restoring full-length ELP1 expression. Delivery of ExSpeU1 via adeno-associated virus serotype 2 (AAV2) to the retina improved ELP1 splicing, rescued RGC loss, and visual function in an FD mouse model. These findings highlight ExSpeU1-mediated splicing correction as a promising therapeutic approach for treating optic neuropathy in FD, offering potential to preserve vision and improve quality of life for patients.
oligonucleotides
2022-08-25 | Engineered U1 snRNAs to modulate alternatively spliced exons.
Alternative splicing accounts for a considerable portion of transcriptomic diversity, as most protein-coding genes are spliced into multiple mRNA isoforms. However, errors in splicing patterns can give rise to mis-splicing with pathological consequences, such as the congenital diseases familial dysautonomia, Duchenne muscular dystrophy, and spinal muscular atrophy. Small nuclear RNA (snRNA) components of the U snRNP family have been proposed as a therapeutic modality for the treatment of mis-splicing. U1 snRNAs offer great promise, with prior studies demonstrating in vivo efficacy, suggesting additional preclinical development is merited. Improvements in enabling technologies, including screening methodologies, gene delivery vectors, and relevant considerations from gene editing approaches justify further advancement of U1 snRNA as a therapeutic and research tool. With the goal of providing a user-friendly protocol, we compile and demonstrate a methodological toolkit for sequence-specific targeted perturbation of alternatively spliced pre-mRNA with engineered U1 snRNAs. We observe robust modulation of endogenous pre-mRNA transcripts targeted in two contrasting splicing contexts, SMN2 exon 7 and FAS exon 6, exhibiting the utility and applicability of engineered U1 snRNA to both inclusion and exclusion of targeted exons. We anticipate that these demonstrations will contribute to the usability of U1 snRNA in investigating splicing modulation in eukaryotic cells, increasing accessibility to the broader research community.
2022-08-09 | Rescue of a familial dysautonomia mouse model by AAV9-Exon-specific U1 snRNA.
Familial dysautonomia (FD) is a currently untreatable, neurodegenerative disease caused by a splicing mutation (c.2204+6T>C) that causes skipping of exon 20 of the elongator complex protein 1 (ELP1) pre-mRNA. Here, we used adeno-associated virus serotype 9 (AAV9-U1-FD) to deliver an exon-specific U1 (ExSpeU1) small nuclear RNA, designed to cause inclusion of ELP1 exon 20 only in those cells expressing the target pre-mRNA, in a phenotypic mouse model of FD. Postnatal systemic and intracerebral ventricular treatment in these mice increased the inclusion of ELP1 exon 20. This also augmented the production of functional protein in several tissues including brain, dorsal root, and trigeminal ganglia. Crucially, the treatment rescued most of the FD mouse mortality before one month of age (89% vs 52%). There were notable improvements in ataxic gait as well as renal (serum creatinine) and cardiac (ejection fraction) functions. RNA-seq analyses of dorsal root ganglia from treated mice and human cells overexpressing FD-ExSpeU1 revealed only minimal global changes in gene expression and splicing. Overall then, our data prove that AAV9-U1-FD is highly specific and will likely be a safe and effective therapeutic strategy for this debilitating disease.
2018-04-24 | Exon-specific U1 snRNAs improve ELP1 exon 20 definition and rescue ELP1 protein expression in a familial dysautonomia mouse model
Familial dysautonomia (FD) is a rare genetic disease with no treatment, caused by an intronic point mutation (c.2204+6T>C) that negatively affects the definition of exon 20 in the elongator complex protein 1 gene (ELP1 also known as IKBKAP). This substitution modifies the 5′ splice site and, in combination with regulatory splicing factors, induces different levels of exon 20 skipping, in various tissues. Here, we evaluated the therapeutic potential of a novel class of U1 snRNA molecules, exon-specific U1s (ExSpeU1s), in correcting ELP1 exon 20 recognition. Lentivirus-mediated expression of ELP1-ExSpeU1 in FD fibroblasts improved ELP1 splicing and protein levels. We next focused on a transgenic mouse model that recapitulates the same tissue-specific mis-splicing seen in FD patients. Intraperitoneal delivery of ELP1-ExSpeU1s-adeno-associated virus particles successfully increased the production of full-length human ELP1 transcript and protein. This splice-switching class of molecules is the first to specifically correct the ELP1 exon 20 splicing defect. Our data provide proof of principle of ExSpeU1s-adeno-associated virus particles as a novel therapeutic strategy for FD.
2016-07-01 | MicroRNA screening identifies a link between NOVA1 expression and low level of IKAP/ELP1 in Familial dysautonomia
Familial dysautonomia (FD) is a rare neurodegenerative disease caused by a mutation in intron 20 of the IKBKAP gene (c.2204+6T>C), leading to tissue-specific skipping of exon 20 and decrease of IKAP/hELP1 synthesis. Small non-coding RNAs, microRNAs (miRNAs) are important posttranscriptional regulators of gene expression and play an essential role in the nervous system development and function. To better understand the neuronal specificity of IKAP/hELP1 loss, we examined expression of miRNAs, in human olfactory ecto-mesenchymal stem cells (hOE-MSCs) from 5 control individuals and 5 FD patients. We profiled the expression of 373 miRNAs using microfluidics and reverse transcription coupled to quantitative polymerase chain reaction (RT-qPCR) on two biological replicate series of hOE-MSC cultures from healthy controls and FD patients. This led to the total identification of 26 dysregulated miRNAs in FD, validating the existence of a miRNA signature in FD. We then selected the nine most discriminant miRNAs for further analysis. The signaling pathways affected by these dysregulated miRNAs were largely within the nervous system. In addition, many targets of these dysregulated miRNAs were previously demonstrated to be affected in FD models. Moreover, we found that four of our nine candidate miRNAs target the neuron-specific splicing factor NOVA1. We demonstrated that overexpression of miR-203a-3p leads to a decrease of NOVA1, counter-balanced by an increase of IKAP/hELP1, supporting a potential interaction between NOVA1 and IKAP/hELP1. Altogether, these results reinforce the choice of miRNAs as potential therapeutic targets and suggest that NOVA1 could be involved as a regulator of FD pathophysiology.
2016-01-13 | Sensory and autonomic deficits in a new humanized mouse model of familial dysautonomia
Familial dysautonomia (FD) is an autosomal recessive neurodegenerative disease that affects the development and survival of sensory and autonomic neurons. FD is caused by an mRNA splicing mutation in intron 20 of the IKBKAP gene that results in a tissue-specific skipping of exon 20 and a corresponding reduction of the inhibitor of kappaB kinase complex-associated protein (IKAP), also known as Elongator complex protein 1. To date, several promising therapeutic candidates for FD have been identified that target the underlying mRNA splicing defect, and increase functional IKAP protein. Despite these remarkable advances in drug discovery for FD, we lacked a phenotypic mouse model in which we could manipulate IKBKAP mRNA splicing to evaluate potential efficacy. We have, therefore, engineered a new mouse model that, for the first time, will permit to evaluate the phenotypic effects of splicing modulators and provide a crucial platform for preclinical testing of new therapies. This new mouse model, TgFD9; IkbkapΔ20/flox was created by introducing the complete human IKBKAP transgene with the major FD splice mutation (TgFD9) into a mouse that expresses extremely low levels of endogenous Ikbkap (IkbkapΔ20/flox). The TgFD9; IkbkapΔ20/flox mouse recapitulates many phenotypic features of the human disease, including reduced growth rate, reduced number of fungiform papillae, spinal abnormalities, and sensory and sympathetic impairments, and recreates the same tissue-specific mis-splicing defect seen in FD patients. This is the first mouse model that can be used to evaluate in vivo the therapeutic effect of increasing IKAP levels by correcting the underlying FD splicing defect.
small molecules
2025-03-09 | Carbidopa: beyond Parkinson's disease.
To revisit the pharmacology and real-world use of carbidopa in the management of autonomic disorders. To identify articles suitable for this review, a search of the PubMed database was conducted in January 2025 using the keywords "Carbidopa," "MK-486," and "L-alpha-methyldopa hydrazine." The pharmacotherapeutic role of carbidopa extends beyond the management of Parkinson's disease. Our literature search revealed the use of carbidopa in three primary autonomic diseases to treat either nausea or symptoms of sympathetic hyperactivity: (1) familial dysautonomia, (2) hyperadrenergic postural orthostatic tachycardia syndrome (POTS), and (3) afferent baroreflex failure (familial or acquired). Even at a dose as high as 600 mg/day, carbidopa was not associated with bothersome side effects in some of the clinical trials on familial dysautonomia. Pre-clinical evidence also suggests in vitro and in vivo inhibition of T-cell activation by carbidopa and a potential therapeutic use in cytokine release syndrome. Current evidence, although limited, suggests that carbidopa has a favorable safety profile. While large, well-designed studies are warranted, observations from case series and small studies suggest that carbidopa could have utility in treating nausea in familial dysautonomia and symptoms of sympathetic hyperactivity in hyperadrenergic postural orthostatic tachycardia syndrome (POTS) and afferent baroreflex failure.
2024-11-28 | Laminin β4 is required for the development of human peripheral sensory neurons.
The extracellular matrix (ECM) is a mixture of glycoproteins and fibrous proteins that provide the biophysical properties necessary to maintain cellular homeostasis. ECM integrity is of particular importance during development, where it allows proper migration and cellular differentiation. Laminins are ECM heterotrimeric proteins consisting of α, β, and γ chains. There are five known α chains, four β chains, and three γ chains. Thus, there are 60 potential combinations for laminin trimers, however only 16 laminin trimers have been identified to date. Furthermore, none of them contain laminin β4 and its function is unknown. Here, we sought to characterize the role of LAMB4 (the gene encoding laminin β4) during human embryonic development of the peripheral sensory nervous system. Using human pluripotent stem cells (hPSCs), we found that LAMB4 is expressed in the ectoderm in the early stages of sensory neuron (SN) specification. SNs, part of the peripheral nervous system, are specialized neurons that detect pain, temperature, and touch. Surprisingly, more than 20 million people in the US have some form of peripheral nerve damage (including SNs), however there are very few treatment options available. Learning about the biology of peripheral neurons will uncover potential new therapeutic targets, thus we focused on understanding the effects of LAMB4 in SNs. First, we knocked out LAMB4 in hPSCs, using CRISPR/Cas9, and found that loss of LAMB4 impairs the migration of the SN progenitors neural crest cells (NCCs) and harms SN development and survival. To assess if LAMB4 has clinical relevance, we studied the genetic disorder Familial Dysautonomia (FD), which specifically affects the peripheral nervous system. FD is caused by a mutation in ELP1 (a component of the Elongator complex) leading to developmental and degenerative defects in SNs. A previous report showed that patients with severe FD harbor additional single nucleotide variants in LAMB4. We found that these variants sharply downregulate the expression of LAMB4 and laminin β4 levels in SNs differentiated from induced pluripotent stem cells (iPSCs) reprogramed from patients with severe FD. Moreover, a healthy ECM is sufficient to rescue the developmental phenotypes of FD, further confirming that ECM defects contribute significantly to the etiology of FD. Finally, we found that LAMB4/laminin β4 is necessary for actin filament accumulation and it interacts with laminin α4 and laminin γ3, forming the laminin-443, a previously unreported laminin trimer. Together, these results show that LAMB4 is a critical, but largely unknown gene required for SN development and survival.
2024-11-20 | Genipin rescues developmental and degenerative defects in familial dysautonomia models and accelerates axon regeneration.
The peripheral nervous system (PNS) is essential for proper body function. A high percentage of the world's population suffers from nerve degeneration or peripheral nerve damage. Despite this, there are major gaps in the knowledge of human PNS development and degeneration; therefore, there are no available treatments. Familial dysautonomia (FD) is a devastating disorder caused by a homozygous point mutation in the gene ELP1. FD specifically affects the development and causes degeneration of the PNS. We previously used patient-derived induced pluripotent stem cells (iPSCs) to show that peripheral sensory neurons (SNs) recapitulate the developmental and neurodegenerative defects observed in FD. Here, we conducted a chemical screen to identify compounds that rescue the SN differentiation inefficiency in FD. We identified that genipin restores neural crest and SN development in patient-derived iPSCs and in two mouse models of FD. Additionally, genipin prevented FD degeneration in SNs derived from patients with FD, suggesting that it could be used to ameliorate neurodegeneration. Moreover, genipin cross-linked the extracellular matrix (ECM), increased the stiffness of the ECM, reorganized the actin cytoskeleton, and promoted transcription of yes-associated protein-dependent genes. Last, genipin enhanced axon regeneration in healthy sensory and sympathetic neurons (part of the PNS) and in prefrontal cortical neurons (part of the central nervous system) in in vitro axotomy models. Our results suggest that genipin has the potential to treat FD-related neurodevelopmental and neurodegenerative phenotypes and to enhance neuronal regeneration of healthy neurons after injury. Moreover, this suggests that the ECM can be targeted to treat FD.
2024-09-04 | Neuronal and glial cell alterations involved in the retinal degeneration of the familial dysautonomia optic neuropathy.
Familial dysautonomia (FD) is a rare genetic neurodevelopmental and neurodegenerative disorder. In addition to the autonomic and peripheral sensory neuropathies that challenge patient survival, one of the most debilitating symptoms affecting patients' quality of life is progressive blindness resulting from the steady loss of retinal ganglion cells (RGCs). Within the FD community, there is a concerted effort to develop treatments to prevent the loss of RGCs. However, the mechanisms underlying the death of RGCs are not well understood. To study the mechanisms underlying RGC death, Pax6-cre;Elp1loxp/loxp male and female mice and postmortem retinal tissue from an FD patient were used to explore the neuronal and non-neuronal cellular pathology associated with the FD optic neuropathy. Neurons, astrocytes, microglia, Müller glia, and endothelial cells were investigated using a combination of histological analyses. We identified a novel disruption of cellular homeostasis and gliosis in the FD retina. Beginning shortly after birth and progressing with age, the FD retina is marked by astrogliosis and perturbations in microglia, which coincide with vascular remodeling. These changes begin before the onset of RGC death, suggesting alterations in the retinal neurovascular unit may contribute to and exacerbate RGC death. We reveal for the first time that the FD retina pathology includes reactive gliosis, increased microglial recruitment to the ganglion cell layer (GCL), disruptions in the deep and superficial vascular plexuses, and alterations in signaling pathways. These studies implicate the neurovascular unit as a disease-modifying target for therapeutic interventions in FD.
2024-06-13 | Marine alkaloid rigidin analogues as potential selective inhibitors of SHP1, a new strategy for cancer immunotherapeutics.
SHP1 is a protein tyrosine phosphatase playing a central role in immunity, cell growth, development, and survival. The inhibition of SHP1 can help in better prognosis in various disorders like breast and ovarian cancer, melanoma, atherosclerosis, hypoxia, hypoactive immune response, and familial dysautonomia. The currently available inhibitors of SHP1 have the side effect of inhibiting the activity of SHP2, which shares >60% sequence similarity with SHP1 but has distinct biological functions. Thus, there is a need to search for novel specific inhibitors of SHP1. The current study uses a combination of virtual screening and molecular dynamic simulations, followed by PCA and MM-GBSA analysis, to screen about 35000 compounds; to predict that two rigidin analogues can potentially selectively inhibit SHP1 but not SHP2. Our studies demonstrate that these rigidin analogues are more potent at inhibiting SHP1 than the commercially available inhibitor NSC-87877. Further, cross-binding studies with SHP2 exhibited poor binding efficiency and lower stability of the complex, thus indicating a specificity of the rigidin analogues for SHP1, which is crucial in preventing side effects due to the diverse physiological functions of SHP2 in cellular signaling, proliferation, and hematopoiesis. Additionally, SHP1 is essential in mediating the inhibitory signaling in antitumor immune cells like NK and T cells. Hence, the rigidin analogues that inhibit SHP1 will potentiate the anti-tumor immune response by the release of inhibitory function of NK cells, thus driving NK activating response, in addition to their intrinsic anti-tumor function. Thus, SHP1 inhibition is a novel double-blade approach towards anti-cancer immunotherapeutics.Communicated by Ramaswamy H. Sarma.
proteins
2024-01-22 | Linking the Extended Autonomic System with the Homeostat Theory: New Perspectives about Dysautonomias
Dysautonomias are conditions in which altered functions of one or more components of the autonomic nervous system (ANS) adversely affect health. This essay is about how elucidating mechanisms of dysautonomias may rationalize personalized treatments. Emphasized here are two relatively new ideas-the "extended" autonomic system (EAS) and the "homeostat" theory as applied to the pathophysiology and potential treatments of dysautonomias. The recently promulgated concept of the EAS updates Langley's ANS to include neuroendocrine, immune/inflammatory, and central components. The homeostat theory builds on Cannon's theory of homeostasis by proposing the existence of comparators (e.g., a thermostat, glucostat, carbistat, barostat) that receive information about regulated variables (e.g., core temperature, blood glucose, blood gases, delivery of blood to the brain). Homeostats sense discrepancies between the information and response algorithms. The presentation links the EAS with the homeostat theory to understand pathophysiological mechanisms of dysautonomias. Feed-forward anticipatory processes shift input-output curves and maintain plateau levels of regulated variables within different bounds of values-"allostasis". Sustained allostatic processes increase long-term wear-and-tear on effectors and organs-allostatic load. They decreaseing thresholds for destabilizing and potentially fatal positive feedback loops. The homeostat theory enables mathematical models that define stress, allostasis, and allostatic load. The present discussion applies the EAS and homeostat concepts to specific examples of pediatric, adolescent/adult, and geriatric dysautonomias-familial dysautonomia, chronic orthostatic intolerance, and Lewy body diseases. Computer modeling has the potential to take into account the complexity and dynamics of allostatic processes and may yield testable predictions about individualized treatments and outcomes.
2023-11-09 | Height, weight, and body mass index in patients with familial dysautonomia
Children with familial dysautonomia (FD) are smaller and grow more slowly than the general population. It is unknown whether this abnormal growth is due to comorbidities that patients with FD live with, or if it is a direct effect of the disease-causing homozygous ELP-1 mutations. Here, we created growth curves for weight, height, and body mass index (BMI) in male and female children with FD to monitor the nutritional status of patients with FD.We used the New York University (NYU) FD Registry which includes data from 680 individuals with FD who were followed longitudinally since birth. We generated sex-specific FD growth charts for three age ranges (birth to 36 months, 2 to 20 years, and 2 to 40 years) and compared them to the general population. We generated Kaplan-Meier curves to test the hypothesis that FD patients with low BMI had shorter survival than the rest of the cohort.Growth charts generated from 591 individuals with FD show that these patients grow more slowly, reach less height, and gain less weight than the general population. The impact of FD on height was more pronounced in girls than in boys. However, both groups showed markedly low weights, which resulted in low BMI. Low weight, but not height, is already evident at birth. In a subpopulation of FD patients, we found that treatment with growth hormone or spinal fusion surgery helped patients achieve the expected growth characteristic of FD patients, but these treatments did not lead FD patients to achieve the growth pattern of the general population. Contrary to our hypothesis, low BMI had no impact on patient survival.Pediatric patients with FD have lower height, weight, and BMI compared to the general pediatric population, but this does not appear to affect survival. Growth curves specific to the FD population are an important tool to monitor growth and nutritional status in pediatric patients with FD when the general population growth curves are of limited use.
2017-06-23 | Pathological Confirmation of Optic Neuropathy in Familial Dysautonomia.
Clinical data suggest that optic neuropathy and retinal ganglion cell loss are the main cause of visual decline in patients with familial dysautonomia, but this has not previously been confirmed by pathological analyses. We studied retinas and optic nerves in 6 eyes from 3 affected patients obtained at autopsy. Analyses included routine neurohistology and immunohistochemistry for neurofilaments, cytochrome c oxidase (COX), and melanopsin-containing ganglion cells. We observed profound axon loss in the temporal portions of optic nerves with relative preservation in the nasal portions; this correlated with clinical and optical coherence tomography findings in 1 patient. Retinal ganglion cell layers were markedly reduced in the central retina, whereas melanopsin-containing ganglion cells were relatively spared. COX staining was reduced in the temporal portions of the optic nerve indicating reduced mitochondrial density. Axonal swelling with degenerating lysosomes and mitochondria were observed by electron microscopy. These findings support the concept that there is a specific optic neuropathy and retinopathy in patients with familial dysautonomia similar to that seen in other optic neuropathies with mitochondrial dysfunction. This raises the possibility that defective expression of the IkB kinase complex-associated protein (IKAP) resulting from mutations in IKBKAP affects mitochondrial function in the metabolism-dependent retinal parvocellular ganglion cells in this condition.
2017-06-07 | RBM24 promotes U1 snRNP recognition of the mutated 5' splice site in the IKBKAP gene of familial dysautonomia.
The 5' splice site mutation (IVS20+6T>C) of the inhibitor of κ light polypeptide gene enhancer in B cells, kinase complex-associated protein (IKBKAP) gene in familial dysautonomia (FD) is at the sixth intronic nucleotide of the 5' splice site. It is known to weaken U1 snRNP recognition and result in an aberrantly spliced mRNA product in neuronal tissue, but normally spliced mRNA in other tissues. Aberrantly spliced IKBKAP mRNA abrogates IKK complex-associated protein (IKAP)/elongator protein 1 (ELP1) expression and results in a defect of neuronal cell development in FD. To elucidate the tissue-dependent regulatory mechanism, we screened an expression library of major RNA-binding proteins (RBPs) with our mammalian dual-color splicing reporter system and identified RBM24 as a regulator. RBM24 functioned as a cryptic intronic splicing enhancer binding to an element (IVS20+13-29) downstream from the intronic 5' splice site mutation in the IKBKAP gene and promoted U1 snRNP recognition only to the mutated 5' splice site (and not the wild-type 5' splice site). Our results show that tissue-specific expression of RBM24 can explain the neuron-specific aberrant splicing of IKBKAP exon 20 in familial dysautonomia, and that ectopic expression of RBM24 in neuronal tissue could be a novel therapeutic target of the disease.
2014-11-19 | Involvement of IKAP in Peripheral Target Innervation and in Specific JNK and NGF Signaling in Developing PNS Neurons
A splicing mutation in the ikbkap gene causes Familial Dysautonomia (FD), affecting the IKAP protein expression levels and proper development and function of the peripheral nervous system (PNS). Here we attempted to elucidate the role of IKAP in PNS development in the chick embryo and found that IKAP is required for proper axonal outgrowth, branching, and peripheral target innervation. Moreover, we demonstrate that IKAP colocalizes with activated JNK (pJNK), dynein, and β-tubulin at the axon terminals of dorsal root ganglia (DRG) neurons, and may be involved in transport of specific target derived signals required for transcription of JNK and NGF responsive genes in the nucleus. These results suggest the novel role of IKAP in neuronal transport and specific signaling mediated transcription, and provide, for the first time, the basis for a molecular mechanism behind the FD phenotype.
gene therapies
2026-04-11 | Prime editing of the common Familial Dysautonomia-causing c.2204 + 6T > C splicing mutation.
Familial Dysautonomia (FD, OMIM #223900) is a rare, life-threatening autosomal recessive neuropathy caused in 99.8% of patients by the c.2204 + 6T > C intronic mutation in the ELP1/IKAP gene. This substitution induces exon 20 skipping, leading to reduced ELP1 expression. While splicing-modulating therapies have shown partial efficacy, a permanent genetic correction remains unavailable. Here, we report the first application of Prime Editing (PE) to rescue the FD-causing IKAP splicing defect. Using a mutant exon-trapping minigene (pTB-IKAP) transiently co-transfected in HEK293T cells with PE2 or PE3 components, we demonstrate a significant increase in exon 20 inclusion, from 19 ± 2% to 48 ± 3% and 60 ± 3%, respectively. Restriction fragment length polymorphism and Sanger sequencing confirmed correction of the mutant allele, with PE3 achieving ~ 10% genomic editing efficiency. Moreover, by targeting ESS2 via a silent A > G substitution, we similarly restored exon inclusion to 50 ± 4%. These findings provide proof-of-principle that prime editing, particularly PE3, can efficiently correct or bypass the ELP1/IKAP c.2204 + 6T > C mutation and restore proper splicing. Given that modest increases in ELP1 expression (5-10% of wild-type) markedly alleviate FD severity in mouse models, our results highlight PE as a promising, potentially curative approach and lay the foundation for future ex-vivo and in vivo studies.
2026-04-10 | Prime editing of the common Familial Dysautonomia-causing c.2204 + 6T > C splicing mutation
Abstract Familial Dysautonomia (FD, OMIM #223900) is a rare, life-threatening autosomal recessive neuropathy caused in 99.8% of patients by the c.2204 + 6T > C intronic mutation in the ELP1/IKAP gene. This substitution induces exon 20 skipping, leading to reduced ELP1 expression. While splicing-modulating therapies have shown partial efficacy, a permanent genetic correction remains unavailable. Here, we report the first application of Prime Editing (PE) to rescue the FD-causing IKAP splicing defect. Using a mutant exon-trapping minigene (pTB-IKAP) transiently co-transfected in HEK293T cells with PE2 or PE3 components, we demonstrate a significant increase in exon 20 inclusion, from 19 ± 2% to 48 ± 3% and 60 ± 3%, respectively. Restriction fragment length polymorphism and Sanger sequencing confirmed correction of the mutant allele, with PE3 achieving ~ 10% genomic editing efficiency. Moreover, by targeting ESS2 via a silent A > G substitution, we similarly restored exon inclusion to 50 ± 4%. These findings provide proof-of-principle that prime editing, particularly PE3, can efficiently correct or bypass the ELP1/IKAP c.2204 + 6T > C mutation and restore proper splicing. Given that modest increases in ELP1 expression (5–10% of wild-type) markedly alleviate FD severity in mouse models, our results highlight PE as a promising, potentially curative approach and lay the foundation for future ex-vivo and in vivo studies.
2026-01-16 | 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 ⁺ ;Elp1 loxp/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 (5.4×10 8 vg) as a promising therapeutic approach for FD-associated optic neuropathy.
2025-10-03 | Peripheral neuron phenotypes of familial dysautonomia are rescued by AAV-mediated gene therapy.
Familial dysautonomia (FD) is a rare genetic, neurodevelopmental and neurodegenerative disorder, where a homozygous mutation in the ELP1 gene is responsible for defects and symptoms found in 99% of patients (1). FD symptoms mainly affect the peripheral nervous system (PNS) (2), including the autonomic and sensory nervous systems (ANS, SNS) (3). The ANS regulates unconscious physiological responses and maintains body homeostasis, such as heart rate, blood pressure, gland secretion, and breathing, which are vital for bodily function. The SNS is the key mediator that processes and relays sensory information from the internal and external environment to the brain, including limb position, temperature, and pain.
2025-09-02 | AAV2-mediated intravitreal delivery of exon-specific U1 snRNA rescues optic neuropathy in a mouse model of familial dysautonomia.
Familial dysautonomia (FD) is a rare autosomal recessive neurodegenerative disorder caused by a splicing mutation in the ELP1 gene. It predominantly affects the sensory and autonomic nervous systems, with progressive vision loss due to optic neuropathy being a universal and debilitating symptom. Retinal pathology in FD involves progressive thinning of the retinal nerve fiber layer (RNFL), resulting from the degeneration of retinal ganglion cells (RGCs). Notably, FD-associated vision loss has a postnatal onset, offering a critical window for therapeutic intervention before severe visual impairment develops in adolescence. Currently, no approved treatments exist to prevent or reverse vision loss in FD. In this study, we present a novel RNA-based therapeutic approach targeting ELP1 pre-mRNA splicing in the retina. We engineered exon-specific U1 small nuclear RNAs (ExSpeU1s) to enhance inclusion of exon 20 in the mutant ELP1 transcripts in the retina, thereby restoring full-length ELP1 expression. Delivery of ExSpeU1 via adeno-associated virus serotype 2 (AAV2) to the retina improved ELP1 splicing, rescued RGC loss, and visual function in an FD mouse model. These findings highlight ExSpeU1-mediated splicing correction as a promising therapeutic approach for treating optic neuropathy in FD, offering potential to preserve vision and improve quality of life for patients.
oligonucleotides
2022-08-25 | Engineered U1 snRNAs to modulate alternatively spliced exons.
Alternative splicing accounts for a considerable portion of transcriptomic diversity, as most protein-coding genes are spliced into multiple mRNA isoforms. However, errors in splicing patterns can give rise to mis-splicing with pathological consequences, such as the congenital diseases familial dysautonomia, Duchenne muscular dystrophy, and spinal muscular atrophy. Small nuclear RNA (snRNA) components of the U snRNP family have been proposed as a therapeutic modality for the treatment of mis-splicing. U1 snRNAs offer great promise, with prior studies demonstrating in vivo efficacy, suggesting additional preclinical development is merited. Improvements in enabling technologies, including screening methodologies, gene delivery vectors, and relevant considerations from gene editing approaches justify further advancement of U1 snRNA as a therapeutic and research tool. With the goal of providing a user-friendly protocol, we compile and demonstrate a methodological toolkit for sequence-specific targeted perturbation of alternatively spliced pre-mRNA with engineered U1 snRNAs. We observe robust modulation of endogenous pre-mRNA transcripts targeted in two contrasting splicing contexts, SMN2 exon 7 and FAS exon 6, exhibiting the utility and applicability of engineered U1 snRNA to both inclusion and exclusion of targeted exons. We anticipate that these demonstrations will contribute to the usability of U1 snRNA in investigating splicing modulation in eukaryotic cells, increasing accessibility to the broader research community.
2022-08-09 | Rescue of a familial dysautonomia mouse model by AAV9-Exon-specific U1 snRNA.
Familial dysautonomia (FD) is a currently untreatable, neurodegenerative disease caused by a splicing mutation (c.2204+6T>C) that causes skipping of exon 20 of the elongator complex protein 1 (ELP1) pre-mRNA. Here, we used adeno-associated virus serotype 9 (AAV9-U1-FD) to deliver an exon-specific U1 (ExSpeU1) small nuclear RNA, designed to cause inclusion of ELP1 exon 20 only in those cells expressing the target pre-mRNA, in a phenotypic mouse model of FD. Postnatal systemic and intracerebral ventricular treatment in these mice increased the inclusion of ELP1 exon 20. This also augmented the production of functional protein in several tissues including brain, dorsal root, and trigeminal ganglia. Crucially, the treatment rescued most of the FD mouse mortality before one month of age (89% vs 52%). There were notable improvements in ataxic gait as well as renal (serum creatinine) and cardiac (ejection fraction) functions. RNA-seq analyses of dorsal root ganglia from treated mice and human cells overexpressing FD-ExSpeU1 revealed only minimal global changes in gene expression and splicing. Overall then, our data prove that AAV9-U1-FD is highly specific and will likely be a safe and effective therapeutic strategy for this debilitating disease.
2018-04-24 | Exon-specific U1 snRNAs improve ELP1 exon 20 definition and rescue ELP1 protein expression in a familial dysautonomia mouse model
Familial dysautonomia (FD) is a rare genetic disease with no treatment, caused by an intronic point mutation (c.2204+6T>C) that negatively affects the definition of exon 20 in the elongator complex protein 1 gene (ELP1 also known as IKBKAP). This substitution modifies the 5′ splice site and, in combination with regulatory splicing factors, induces different levels of exon 20 skipping, in various tissues. Here, we evaluated the therapeutic potential of a novel class of U1 snRNA molecules, exon-specific U1s (ExSpeU1s), in correcting ELP1 exon 20 recognition. Lentivirus-mediated expression of ELP1-ExSpeU1 in FD fibroblasts improved ELP1 splicing and protein levels. We next focused on a transgenic mouse model that recapitulates the same tissue-specific mis-splicing seen in FD patients. Intraperitoneal delivery of ELP1-ExSpeU1s-adeno-associated virus particles successfully increased the production of full-length human ELP1 transcript and protein. This splice-switching class of molecules is the first to specifically correct the ELP1 exon 20 splicing defect. Our data provide proof of principle of ExSpeU1s-adeno-associated virus particles as a novel therapeutic strategy for FD.
2016-07-01 | MicroRNA screening identifies a link between NOVA1 expression and low level of IKAP/ELP1 in Familial dysautonomia
Familial dysautonomia (FD) is a rare neurodegenerative disease caused by a mutation in intron 20 of the IKBKAP gene (c.2204+6T>C), leading to tissue-specific skipping of exon 20 and decrease of IKAP/hELP1 synthesis. Small non-coding RNAs, microRNAs (miRNAs) are important posttranscriptional regulators of gene expression and play an essential role in the nervous system development and function. To better understand the neuronal specificity of IKAP/hELP1 loss, we examined expression of miRNAs, in human olfactory ecto-mesenchymal stem cells (hOE-MSCs) from 5 control individuals and 5 FD patients. We profiled the expression of 373 miRNAs using microfluidics and reverse transcription coupled to quantitative polymerase chain reaction (RT-qPCR) on two biological replicate series of hOE-MSC cultures from healthy controls and FD patients. This led to the total identification of 26 dysregulated miRNAs in FD, validating the existence of a miRNA signature in FD. We then selected the nine most discriminant miRNAs for further analysis. The signaling pathways affected by these dysregulated miRNAs were largely within the nervous system. In addition, many targets of these dysregulated miRNAs were previously demonstrated to be affected in FD models. Moreover, we found that four of our nine candidate miRNAs target the neuron-specific splicing factor NOVA1. We demonstrated that overexpression of miR-203a-3p leads to a decrease of NOVA1, counter-balanced by an increase of IKAP/hELP1, supporting a potential interaction between NOVA1 and IKAP/hELP1. Altogether, these results reinforce the choice of miRNAs as potential therapeutic targets and suggest that NOVA1 could be involved as a regulator of FD pathophysiology.
2016-01-13 | Sensory and autonomic deficits in a new humanized mouse model of familial dysautonomia
Familial dysautonomia (FD) is an autosomal recessive neurodegenerative disease that affects the development and survival of sensory and autonomic neurons. FD is caused by an mRNA splicing mutation in intron 20 of the IKBKAP gene that results in a tissue-specific skipping of exon 20 and a corresponding reduction of the inhibitor of kappaB kinase complex-associated protein (IKAP), also known as Elongator complex protein 1. To date, several promising therapeutic candidates for FD have been identified that target the underlying mRNA splicing defect, and increase functional IKAP protein. Despite these remarkable advances in drug discovery for FD, we lacked a phenotypic mouse model in which we could manipulate IKBKAP mRNA splicing to evaluate potential efficacy. We have, therefore, engineered a new mouse model that, for the first time, will permit to evaluate the phenotypic effects of splicing modulators and provide a crucial platform for preclinical testing of new therapies. This new mouse model, TgFD9; IkbkapΔ20/flox was created by introducing the complete human IKBKAP transgene with the major FD splice mutation (TgFD9) into a mouse that expresses extremely low levels of endogenous Ikbkap (IkbkapΔ20/flox). The TgFD9; IkbkapΔ20/flox mouse recapitulates many phenotypic features of the human disease, including reduced growth rate, reduced number of fungiform papillae, spinal abnormalities, and sensory and sympathetic impairments, and recreates the same tissue-specific mis-splicing defect seen in FD patients. This is the first mouse model that can be used to evaluate in vivo the therapeutic effect of increasing IKAP levels by correcting the underlying FD splicing defect.
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Drug Discovery Landscape
3 orphan drug designations for Familial dysautonomia.
3 orphan drug designations for Familial dysautonomia.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
2-[(2S)-2-aminopropyl]-3,5-dichloro-N-(2-thienylmethyl)thieno[3,2-b]pyridin-7-amine | small molecules | FDA | 2024-10-24 | — | Tikun Therapeutics Inc. |
Recombinant adeno-associated virus serotype 2 containing the human ELP1 gene, driven by the U1a promoter | gene therapies | FDA | 2024-09-09 | — | Tikun Therapeutics Inc. |
O-(3-piperidino-2-hydroxy-1-propyl)-nicotinic acid amidoxime dihydrochloride | small molecules | FDA | 2020-10-08 | — | Mitochon Technologies Kft. |
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