B6-hELP1 Mice

Catalog Number: I001203

Strain Name: C57BL/6NCya-Elp1^tm1(hELP1)/Cya

Genetic Background: C57BL/6NCya

Reproduction: Homozygote x Homozygote

One of Cyagen’s HUGO-GT^TM (Humanized Genomic Ortholog for Gene Therapy) Strains

Strain Description

Familial dysautonomia (FD) is a rare autosomal recessive genetic neurological disorder. Patients with FD exhibit symptoms such as excessive sweating, intermittent hypertension, drooling, abnormal glandular secretion, difficulty swallowing, urinary and fecal incontinence, breathing difficulties, periodic vomiting, and physical developmental abnormalities, including intellectual disability and osteoporosis. FD primarily results from underdeveloped cervical sympathetic ganglia, with mutations in the ELP1 gene being a significant genetic factor. The ELP1 gene, also known as IKBKAP, encodes components of the elongation complex essential for tRNA modification. This widely expressed protein plays a crucial role in neuronal development and function. Mutations in both copies of the ELP1 gene can lead to decreased or absent ELP1 protein levels, causing neuronal damage and potentially contributing to FD symptoms.

There is no mature cure for FD. Treatment primarily focuses on symptomatic relief and supportive care to alleviate symptoms and prevent complications. Gene therapy, a promising approach, targets the underlying cause of FD---gene mutations---enhancing treatment efficiency and persistence. This field is expected to be the next breakthrough. At present, the ELP1 targeted drug pipeline has begun to be laid out. The preclinical animal models are mostly transgenic humanized mice. Compared with randomly inserted, humanized region-restricted transgenic humanized mice, more scientific and efficient whole-genome humanized animal models will help promote the potential therapy targeting ELP1 to accelerate into the clinical stage. This strain is a mouse Elp1 gene humanized model and can be used to research Familial dysautonomia (FD). The homozygous B6-hELP1 mice are viable and fertile. In addition, based on the independently developed TurboKnockout fusion BAC recombination technology, Cyagen can also generate hot mutation (ELP1 IVS20+6T>C) models based on this strain and provide customized services for specific mutations.

Strain Strategy

Figure 1. Gene editing strategy of B6-hELP1 mice. The sequences from the ATG start codon to the TGA stop codon of the endogenous mouse Elp1 gene were replaced with the sequences from the ATG start codon to the TGA stop codon of the human ELP1 gene.

Application

• Research on the pathogenic mechanism of Familial dysautonomia (FD);
• Preclinical research of ELP1-targeted drugs.
  
  

Validation Data

1. Expression of human ELP1 gene and mouse Elp1 gene

Figure 2. Gene expression analysis in the cerebral cortex, kidney, liver, skeletal muscle, and heart of 7-week-old male homozygous B6-hELP1 mice and wild-type (WT) mice (n=4). RT-qPCR results reveal significant expression of the human ELP1 gene in the cerebral cortex, kidney, liver, skeletal muscle, and heart of B6-hELP1 mice, while the mouse Elp1 gene is not expressed. In wild-type mice, only the mouse Elp1 gene is detected, with no expression of the human ELP1 gene (ND: Not detected).

Expanded Information: The Rare Disease Data Center (RDDC)

1. Basic information about the ELP1 gene

https://rddc.tsinghua-gd.org/gene/8518

2. ELP1 clinical variants

3. Disease introduction

Familial dysautonomia (FD) is a rare autosomal recessive genetic neurological disorder. Patients with FD exhibit symptoms such as excessive sweating, intermittent hypertension, drooling, abnormal glandular secretion, difficulty swallowing, urinary and fecal incontinence, breathing difficulties, periodic vomiting, and physical developmental abnormalities, including intellectual disability and osteoporosis. FD primarily results from underdeveloped cervical sympathetic ganglia, with mutations in the IKBKAP gene being a significant genetic factor.

4. ELP1 gene and mutations

The ELP1 gene, also known as IKBKAP, encodes components of the elongation complex essential for tRNA modification. This widely expressed protein plays a crucial role in neuronal development and function. Mutations in both copies of the ELP1 gene can lead to decreased or absent ELP1 protein levels, causing neuronal damage and potentially contributing to FD symptoms.

Over 99% of FD patients carry two identical copies of the ELP1 gene mutation, specifically the 5’ splice site mutation IVS20+6T>C within intron 20. This mutation disrupts base pairing between U1 small nuclear ribonucleoprotein (U1-snRNP) and the intron 20 donor splice site, resulting in exon 20 skipping and translating a truncated 79 kDa protein. While this mutation may reduce the quantity of ELP1 protein, the outcomes vary across different cell types. In some cells, it produces protein levels close to normal, while in others, especially brain cells, the protein is nearly absent ^[1].

5. Function of non-coding DNA sequences

A common mutation in the non-coding region is the 5’ splice site mutation IVS20+6T>C in intron 20 ^[1].

6. ELP1-targeted gene therapy

There is no mature cure for FD. Treatment primarily focuses on symptomatic relief and supportive care to alleviate symptoms and prevent complications. Gene therapy, a promising approach, targets the underlying cause of FD---gene mutations---enhancing treatment efficiency and persistence. This field is expected to be the next breakthrough. At present, the ELP1 targeted drug pipeline has begun to be laid out. The ASO drug (PTC-0405403) developed by PTC Therapeutics and other institutions is currently in the preclinical stage. This drug corrects the splicing defect of ELP1 by targeting the mutation IVS20+6T>C to treat the disease. The preclinical research uses transgenic humanized mice TgFD9;Elp1Δ20/flox as the research object ^[2]. Compared with randomly inserted, humanized region-restricted transgenic humanized mice, more scientific and efficient whole-genome humanized animal models will help promote the potential therapy targeting ELP1 to accelerate into the clinical stage. In response to the research on the mechanism and pharmacology, Cyagen has also independently developed a disease model carrying ELP1 IVS20+6T>C mutation.

7. Summary

The ELP1 gene is an important pathogenic gene for Familial dysautonomia (FD). ELP1 gene humanized mice from Cyagen can be used for preclinical research on FD, and customized services can also be provided for different point mutations.

References

[1] Carmel, I, Tal, et al. Comparative analysis detects dependencies among the 5' splice-site positions[J].RNA -CAMBRIDGE-, 2004.

[2] Morini E, Chekuri A, Logan EM, Bolduc JM, Kirchner EG, Salani M, Krauson AJ, Narasimhan J, Gabbeta V, Grover S, Dakka A, Mollin A, Jung SP, Zhao X, Zhang N, Zhang S, Arnold M, Woll MG, Naryshkin NA, Weetall M, Slaugenhaupt SA. Development of an oral treatment that rescues gait ataxia and retinal degeneration in a phenotypic mouse model of familial dysautonomia. Am J Hum Genet. 2023 Mar 2;110(3):531-547. doi: 10.1016/j.ajhg.2023.01.019. Epub 2023 Feb 20. PMID: 36809767; PMCID: PMC10027479.