Activating GNE Enzyme for GNE Myopathy Treatment

Mokako Yoshioka believes activating the GNE enzyme can provide a continuous supply of sialic acid for better myopathy treatment.

### Activating GNE for Myopathy Treatment
Mokako Yoshioka is studying GNE myopathy at the National Center of Neurology and Psychiatry in Tokyo. The project's focus is on finding **small molecules to activate the GNE enzyme**, aiming to provide a **continuous supply of sialic acid** for effective myopathy treatment. Animal experiments and clinical trials have shown that sialic acid supplementation can **prevent and improve skeletal muscle atrophy and weakness** in symptomatic mice, but **rapid metabolization of sialic acid** poses a challenge for human therapy.

### Serum Salicylic Acid Concentration in Patients
Serum salicylic acid concentration did not increase significantly after single or three-time administrations in three patients. The continuous supplementation of salicylic acid in mice, through frequent drinking, was **key to its high efficacy**. The extended-release tablet form of salicylic acid showed promise in **elevating serum concentration** in patients, but the efficacy was not enough to **improve symptoms**, leading to the **termination of its development for treatment**.

### Activating Gene Therapy for GMA Patients
The speaker discusses a **continuous supply of silicic acid** and the challenges of traditional drug development for gene therapy. They opt for drug repositioning as a **faster and more economical method**, using high-throughput screening and in silico screening with a supercomputer for **structure-based drug candidate identification**. The 3D structure of the DNA molecule is constructed, revealing a **stable dimer crucial for enzyme reaction**, with the protein gene encoding **two enzymatic activities**.

### Targeting Enzyme Activity for Manak Production
The study focuses on targeting the **GNE enzyme's activity** to increase manak production, using two approaches: inhibiting **CMP New York binding** and stabilizing **oligomerization**. Small compounds were identified to fit the cavity of the **CMP New York binding site**, with in silico drug screening used to select potential inhibitors. The effectiveness of these compounds in increasing GNE enzyme activity was measured through a new method, showing that the mutant GNE enzyme with **D207B mutation** produced **significantly less manak** compared to the wild type.

### The Role of Oligomerization in Enzyme Activity and Monarch Production
Mutant G and E genes did not increase Monarch production despite adding selected compounds. CMP Newark acted as a competitor, **decreasing Monarch production** instead of increasing it. Oligomerization is crucial for enzyme activity, and mutants with oligomerization failure showed **low enzyme activity**, suggesting that **stabilizing organization and accelerating polymerization** could potentially **elevate enzyme activity and increase Monarch production**.

### Targeting Oligomerization: Compounds for Enzyme Activity
The study focuses on small compounds to counteract the oligomerization of a mutant gene associated with enzyme activity. Candidate compounds were found to **increase enzyme production in the mutant**, though not to wild type levels. The research aims to **select the best candidates for further screening** and to confirm their effectiveness in **increasing enzyme activity and salicylic acid production in patient cells**.

### Activating GNE for Improved Treatment of GNE Myopathy: A Novel Approach
* 👩 ‍🔬 Mokako Yoshioka presents her project on activating endogenous mutated GNE products through small compounds, emphasizing the **potential for treating GNE myopathy**.
* 🇯🇵 Currently studying at the National Center of Neurology and Psychiatry in Tokyo, Japan, Yoshioka highlights the **beauty of the center**, especially during **cherry blossom and autumn seasons**.
* 🧬 GNE myopathy, an adult-onset distal myopathy caused by mutations in the GNE gene, typically shows symptoms in the **third decade of life** and leads to **muscle weakness and atrophy** due to **decreased sialic acid production**.
* 💡 The project aims to find small molecules that **activate the GNE enzyme**, as this could enable a **continuous supply of sialic acid**, which is essential for **effective treatment**.
* 💊 While initial trials with oral sialic acid supplementation showed promise in mice, **rapid metabolization in humans** posed challenges, leading to the development of **extended-release tablets** to maintain serum levels.
* 📉 Clinical trials indicated that while serum sialic acid concentrations were **elevated with the extended-release tablets**, the efficacy in **improving symptoms was insufficient**, prompting a search for **better solutions**.
* 🔍 Yoshioka's team is utilizing in silico screening with a supercomputer to identify compounds that **stabilize GNE enzyme oligomerization**, which is **crucial for its activity**, and preliminary results show some compounds may **enhance enzyme function**.
* 🤝 Acknowledging the support of mentors and collaborators, Yoshioka concludes that **activating the GNE enzyme through drug repositioning** could provide a **promising new therapeutic strategy** for GNE myopathy.

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2022 Dr. Wakako Yoshioka: "Activation of Endogenous Mutated GNE Product by Small Compound"

2022 Dr. Wakako Yoshioka: "Activation of Endogenous Mutated GNE Product by Small Compound"