TS-002303 — WHO: Scott Harper WHAT: RNAi therapy WHY: DNM1 Developmental and Epileptic Encephalopathy (DEE) HOW: (from IDF) The DNM1 gene encodes dynamin-1, a large GTPase involved in clathrin-mediated endocytosis of synaptic vesicles in neurons and in related processes. Dynamin monomers assemble into multimers that interact with each other and with various other proteins to form ring structures for GTPase-catalyzed membrane scission. Dominant mutations in one allele of DNM1 cause neurological disease in humans and mice. Children with DNM1 mutations suffer from intractable conditions manifesting as early-onset seizures, global developmental delay, profound intellectual disability, lack of speech, muscular hypotonia, dystonia, and spasticity. As is the case with many severe DEEs, affected individuals do not respond well to antiepileptic drugs, leaving >80 % of patients with intractable seizures and little to no improvement of the severely debilitating other neurological features. At least 20 de novo pathogenic DNM1 variants have been identified, and all are presumed to operate with dominant effect, most likely by interfering with the assembly or function of normal dynamin-1 monomers. Importantly, knockout studies in mice support that at least 50% normal DNM1 levels are required, as homozogous DNM1 null animals die by postnatal day 8. We propose that a successful gene therapy approach must eliminate or reduce the expression or translation of the mutant DNM1 variant mRNA or protein, while still enabling expression of the remaining wild-type allele. We are pursuing two different approaches to accomplish this: (1) isoform-specific silencing of mutant DNM1 transcripts; (2) a knockdown-and-replace strategy; expressing exogenous wildtype Dnm1 via AAV while eliminating endogenous Dnm1 mRNA entirely. We already filed an IDF and provisional patent application on approach 1. This IDF covers the knockdown-and-replace strategy. In brief, we will develop artificial microRNAs that non-selectively knockdown both mutant and wild-type DNM1 alleles using RNAi, while at the same time adding back an RNAi-resistant, wild-type DNM1 cDNA. We will test this in mouse models of DNM1-related DEE in the Frankel lab at Columbia University.

TS-002282 — Rare variants in genes GRIN2A, GRIN2B and GRIN2D are associated with severe childhood-onset neurological diseases like epileptic encephalopathies and autism. There are no treatments for these chronic disorders that cause developmental delays or developmental skill loss. Researcher and principal investigator, Scott Harper, at Nationwide Children’s Hospital developed a genetic therapy for GRIN2 disease through a knockdown-and-replace strategy by using artificial microRNAs that non-selectively knockdown both mutant and wildtype GRIN2A alleles using RNAi and adding back an RNAi-resistant, wildtype GRIN2A cDNA. The therapy will express functional GRIN2 exogenously while eliminating endogenous GRIN2 mRNA entirely through AAV delivery.

TS-002280 — **based on incomplete invention disclosure What: RNAi Therapy Why: Developmental and Epileptic Encephalopathy --> currently no treatment for DNM1- related How: Decrease expression of pathogenic variants in the dynamin-1 gene (DNM1 gene) which causes a particularly severe form of dominant developmental and epileptic encephalopathy (DEE)

TS-002228 — Charcot-Marie-Tooth Disease (CMT), a group of inherited disorders causing peripheral nerve damage, affects 1 in 3,300 people worldwide. Individuals experience weakness in their muscles, sensation loss and muscle contractions in their feet, legs, arms and hands. Recent research shows overexpression of tRNA-glycine can ease peripheral neuropathy caused by Glycyl-tRNA synthetase (GARS) mutations. Principal investigator Scott Harper of Nationwide Children’s Hospital’s Center for Gene Therapy developed a gene therapy to overexpress relevant tRNAs associated with various tRNA synthetase-related disorders like CMT. This therapy would improve an individual’s quality of life by lessening the pain, weakness, and numbness from the nerve damage.

TS-002226 — Developmental and Epileptic Encephalopathy (DEE) are a group of epilepsies referring to drug-resistant seizures and encephalopathy (significant developmental delays or the loss of developmental skills). Principal Investigator, Scott Harper, of Nationwide Children’s Hospital’s Center for Gene Therapy created a RNAi therapy that decreases the expression of pathogenic variants in the KCNQ3 gene that causes DEE. The therapy uses AAV9 vectors to deliver newly designed microRNA sequences to target the KCNQ3 gene.

TS-002175 — The third most common type of muscular dystrophy, Facioscapulohumeral Muscular Dystrophy (FSHD), affects over 870,000 individuals worldwide by causing debilitating pain, muscle weakness, fatigue along with many other symptoms in their face, shoulders, upper arms and lower legs. Researchers at Nationwide Children’s Hospital created a treatment using Salvianolic Acid (SAA) as a drug therapy for neuromuscular disorders including FSHD.

TS-002174 — Currently, no cure exists for Charcot-Marie tooth type 1B (CMT1B). Inventors and specialists in Gene Therapy at Nationwide Children’s Hospital invented a methodology along with sequences for using microRNAs (miRNA) to inhibit and replace abnormal expressions of the myelin protein zero (MPZ) gene. Affecting 1 in 30,000 people, CMT1B is caused by more than 200 mutations of the MPZ, the essential protein needed for a healthy and efficient peripheral nervous system. The accumulation of mutant MPZ genes will result in, but not limited to, muscle weakness, atrophy, lost of sensation in the lower legs and feet and sensory loss.

TS-002006 — Overexpression of the GRIN2D gene can cause Developmental and Epileptic Encephalopathy (DEE) in which individuals may experience developmental delays or intellectual disabilities, epilepsy, abnormal muscle tone, movement disorders, autism spectrum disorder and cortical visual impairment. Currently, only supportive care is available. Genetic Researchers at Nationwide Children’s Hospital developed a RNAi gene therapy to treat epilepsy caused by GRIN2D. They propose decreasing the expression of GRIN2D through a gene-level specific reagent which will knock down the mRNA containing the variant postnatally. As a result, reducing the possibility of children developing GRIN2D-related DEE.

TS-000199 — Facioscapulohumeral Muscular Dystrophy (FSHD) is the third most common muscular dystrophy, affecting 1 in 20,000 individuals. There is no current treatment for FSHD; therefore, animal models of the disease are essential for testing potential therapies. Researchers at Nationwide Children’s Hospital have developed a mouse model that recapitulates the FSHD phenotype and develops myopathy. This is an inducible FSHD mouse model that stably expresses the disease-causing gene, DUX4, from the mouse genome using the human DUX4 promoter. Importantly, in comparison to other FSHD mouse models, this particular inducible model circumvents lethality and leakiness problems seen in past models of the disease. Available for purchase through Jax Labs jax.org Stock No: 032779 Potential Applications/Markets: The FSHD field is lacking a good mouse model that recapitulates FSHD phenotypes and develops myopathy. Opportunity/Seeking: Licensing