Columbia Technology Ventures

Knockdown-and-replace gene therapy for DNM1 developmental and epileptic encephalopathy

This technology describes a method for selectively eliminating dynamin-1 (DNM1) variants for the treatment of DNM1-associated neurological diseases such as severe developmental and epileptic encephalopathy (DEE).

Unmet Need: Therapy for patients with DNM1 mutations that are unresponsive to antiepileptic drugs

Mutations in dynamin-1 (DNM1) result in severe developmental and epileptic encephalopathy (DEE), with most pediatric patients unresponsive to current antiepileptic drugs. For a majority of patients traditional antiepileptic drugs are not effective, leaving >80% of patients with intractable seizures. Approximately 20 pathogenic DNM1 variants have been identified and attributed to playing a causal role in the neurological symptoms of the disease. Therefore, a gene therapy approach targeting pathogenic DNM1 may provide an effective treatment approach.

The Technology: Selective gene therapy that restores wildtype expression of DNM1

This method selectively eliminates DNM1 variants for the treatment of DNM1-associated neurological diseases. Artificial microRNAs are used to eliminate DNM1 alleles in a nonspecific manner, thereby knocking down DNM1 expression entirely. Simultaneously, exogenous DNM1 are expressed via adeno-associated virus (AAV) delivery, thereby rescuing wild-type expression of DNM1. This combinatorial treatment selectively targets pathogenic variants while restoring the function of wildtype DNM1, which may allow for more effective treatment of DEE.

Applications:

  • Treatment of dynamin-1 associated diseases
  • Research model for studying dynamin 1
  • General method of treating diseases associated with dominant mutations

Advantages:

  • Permanent cure of neurological diseases
  • Eliminates or reduces the expression of mutant DNM1 while simultaneously enables expression of wildtype DNM1
  • Selective for pathogenic variants of DNM1 while restoring the wildtype expression

Lead Inventor:

Wayne N. Frankel, Ph.D.

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