Advancements in AAV Gene Therapy for GNE Myopathy

Dr. Goodell is developing a dual promoter AAV gene therapy to treat GNE myopathy effectively.

### Advancements in AAV Gene Therapy for GNE Myopathy: Insights from Dr. Julie Goodell
* 👋 Welcome to the GE nem Symposium speaker series, where Dr. Julie Goodell, an assistant professor at the University of Washington, presents her work on **AAV gene therapy for GNE myopathy**, a condition caused by mutations in the **GNE gene**.
* 🎓 Dr. Goodell's academic journey includes degrees from Dartmouth and a PhD focused on **gene therapy** at the University of Pennsylvania, leading to her current research on **muscle gene therapy** for conditions like **Duchenne muscular dystrophy**.
* 🔬 Her presentation highlights the importance of developing a **dual promoter** that expresses the **GNE gene** in both muscle and liver, aiming to utilize liver expression to **enhance muscle correction**.
* 📊 The experimental design involves creating tandem expression cassettes, with initial results indicating that certain combinations of liver and muscle regulatory elements **significantly improve expression in both tissues**.
* 💡 Dr. Goodell emphasizes the selection of AAV vectors, particularly the promising **AAV myo**, which shows **effective transduction in muscle at significantly lower doses** than previously used, potentially **enhancing safety in clinical applications**.
* 💉 The proposed delivery method for the therapy is **intravenous**, allowing for **widespread transduction of muscle and liver tissues**, which is **crucial for the treatment's effectiveness**.
* 🗓 Dr. Goodell anticipates that clinical trials for GNE myopathy could begin **within two to three years**, although the timeline is subject to **regulatory approvals and funding challenges**.
* 🤝 The collaborative nature of this research, supported by the **No Muscular Disease Foundation**, underscores the collective effort in advancing **gene therapy solutions for GNE myopathy**, with hopes for **market availability within the next decade**.

### AAV Gene Therapy for GNE Myopathy
Dr. Julie Goodell, an assistant professor at the University of Washington, is working on AAV gene therapy for GNE myopathy, focusing on **promoter development and AAV serotype screening**. GNE myopathy is caused by mutations in the GNE gene, which is crucial for **sialic acid production in cells**. The gene therapy aims to **replace the GNE gene** and has shown promising results in mouse models by demonstrating that **liver expression of the GNE protein** can help **correct muscle deficiencies**.

### Designing a Gene Therapy Cassette for GNE Gene Replacement
The gene therapy cassette requires a promoter and a transgene, with **GNE1 being the chosen transgene** for GNE gene replacement. The study aims to create tandem expression cassettes for **dual expression of GNE in skeletal muscle and liver**, addressing **safety concerns and promoter silencing**. Experimental results show that the combination of muscle and liver regulatory elements **increases expression in both tissues**, with the goal of using this data to **design an effective gene therapy**.

### Gene Therapy: Vector Selection and Muscle Expression
Tech 1B, 3, 4.8, and 4.10 lead to **increased expression in both muscle and liver**, with Tech 4.8 being chosen for the gene cassette due to its **balanced expression**. The adeno-associated viral (AAV) vector is selected for its **non-pathogenic nature** and ability to **transduce muscle and liver cells**. However, the high doses of AAV used in clinical trials have been associated with **severe adverse events and rare fatalities**, highlighting the need for **dose reduction to improve safety**.

### Safer Gene Therapy for Muscle Diseases
The treatment's safety is being improved by **reducing doses** and carefully choosing the **promoter and vector**. AAV Myo, a newly designed AAV serotype, is being tested in the lab and has shown to be **effective at 10 times lower doses** than currently used for muscle diseases. The plan is to deliver the treatment **intravenously** to transduce muscles and the liver throughout the body.

### Timeline for GNE Myopathy Clinical Trials
The Luck Lab is leading the effort to develop a GNE myopathy treatment, with a goal to **start clinical trials in 2-3 years**, although this timeline is ambitious. The process from clinical trial to market approval could take an additional **5 years**, with a hopeful target of having a treatment available within **10 years**. Multiple labs are involved in the consortium effort, and **funding is crucial for progressing to clinical trials**.

### Challenges in Clinical Trials for Gene Therapy
Funding for clinical trials is a major hurdle, with costs reaching **hundreds of thousands of dollars**. The adult onset of the disorder and its slow progression make it **less attractive to biotech companies**. The size of the tech cassette is **1,000 base pairs**, and the overall gene therapy construct is **under 4.7 KB**, while biodistribution studies in mice are planned to assess **expression in immune cells**.

### Gene Therapy for GNE Myopathy: Insights and Challenges
Codon optimization is being pursued to **increase translational efficiency** in GNE myopathy gene therapy, although it's not part of the NDF-funded study. Complete recovery from gene therapy is unlikely, but early treatment may lead to **significant function restoration**. The gene therapy is expected to be a **one-time treatment**, with effects potentially **lasting a decade or more**, while efforts are being made to establish mechanisms for **safe re-treatment** in the future.

### FDA's Perspective on Myo AV and AV Mayo
The FDA is likely to view Myo AV and AV Mayo as variants of AAV9, but the recent **adverse events in gene therapy** may necessitate primate studies for safety. AI protein synthesis and modeling for protein folding are not within the speaker's team's scope, but other groups are exploring these areas. Careful consideration is needed when studying GNE overexpression, as blocking its **negative feedback** could lead to **toxic levels of extracilic acid**.

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2022 NDF GNEM Speaker Series with Dr Julie Crudele Developing An AAV Gene Therapy For GNEM