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:
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.
2026-01-16 | 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.
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.
2026-01-16 | 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.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
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. |
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI's forecasts to outperform average preclinical success rates. Whether you're expanding your R&D pipeline, evaluating a partnership, or simply have a question — we'd love to hear from you.