An antisense oligonucleotide therapy for KCNT1 based epileptic encephalopathies

Information

  • Research Project
  • 10266821
  • ApplicationId
    10266821
  • Core Project Number
    R43NS117263
  • Full Project Number
    5R43NS117263-02
  • Serial Number
    117263
  • FOA Number
    PA-19-272
  • Sub Project Id
  • Project Start Date
    9/30/2020 - 4 years ago
  • Project End Date
    7/31/2022 - 2 years ago
  • Program Officer Name
    CAPORELLO, EMILY LAURA
  • Budget Start Date
    8/1/2021 - 3 years ago
  • Budget End Date
    7/31/2022 - 2 years ago
  • Fiscal Year
    2021
  • Support Year
    02
  • Suffix
  • Award Notice Date
    9/10/2021 - 3 years ago

An antisense oligonucleotide therapy for KCNT1 based epileptic encephalopathies

Project Summary: Malignant Migrating Partial Seizures of Infancy (MMPSI) is a severe epileptic encephalopathy (EE) resulting in intractable seizures and severe developmental delays. It manifests early in childhood and can have devastating impacts on affected individuals and their families. Mutations in a gene called KCNT1 have been associated with MMPSI. KCNT1 encodes an ion channel, highly expressed in the nervous system, that regulates neuronal excitability. Current therapies for KCNT1-based MMPSI include a variety of anti-epileptic drugs with limited efficacies in the clinic. More importantly, these drugs do not target the underlying genetic cause of the disease. Antisense oligonucleotide (ASO) therapies may, however, provide a novel therapeutic strategy for targeting mutant KCNT1 channels expressed in this disorder. Recent clinical demonstrations of ASO efficacy in other genetic diseases, such as spinal muscular atrophy and muscular dystrophy, have validated this approach and given hope to patients. ASOs are short, synthetic stretches of modified genetic material that can be designed to recognize and knockdown specific gene products. ASO drugs are administered directly into the central nervous system by injection into the fluid surrounding the spinal cord. In this research program, ASOs will be designed and tested in human cell-based models of KCNT1-linked EEs with the goal of knocking down KCNT1 gene products, including those containing the malignant mutation. ASOs will be designed to assess targeting of many regions of the KCNT1 gene which would enable evaluation of gene knockdown independent of the location of the mutation. Disease models have been previously characterized by electrophysiological screening and include patient-derived neuronal cells, as well as control cell lines that have been genetically-engineered to express mutant KCNT1. In a subsequent phase of the research program, the final candidate ASOs from this phase will be further optimized in in vivo models and ultimately developed as therapies for KCNT1-based EEs. Ultimately, the proposed research stands to benefit this specific population of patients with KCNT1 mutations, who suffer from devastating seizures and neurological deficits, as well as provide additional traction for the development of other ASO-based therapies for severe genetic diseases.

IC Name
NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
  • Activity
    R43
  • Administering IC
    NS
  • Application Type
    5
  • Direct Cost Amount
  • Indirect Cost Amount
  • Total Cost
    76089
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    853
  • Ed Inst. Type
  • Funding ICs
    NINDS:76089\
  • Funding Mechanism
    SBIR-STTR RPGs
  • Study Section
    ZRG1
  • Study Section Name
    Special Emphasis Panel
  • Organization Name
    Q-STATE BIOSCIENCES, INC.
  • Organization Department
  • Organization DUNS
    078880703
  • Organization City
    CAMBRIDGE
  • Organization State
    MA
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    021394238
  • Organization District
    UNITED STATES