Zaid Memon

Green Fellows project abstract:

Prader-Willi Syndrome (PWS) is a rare neurodevelopmental disease with a prevalence estimated to be approximately 1 in 12,000-20,000. This disorder results in small hands and feet, abnormal growth and body composition, hypotonia at birth causing lethargy and poor suck reflex, insatiable hunger resulting in extreme obesity later in childhood and adulthood, and delayed developmental motor and language milestones. This disease affects males and females with an equal frequency, but despite all these symptoms people with PWS can live a close to normal lifespan if they implement weight control. Currently, there is no cure for PWS: most current treatment focuses on managing the medical and developmental issues. However, recently animal models have shown potential therapeutic benefits by inhibiting the protein euchromatic histone lysine N-methyltransferase-2 or EHMT2. Although the results of this inhibition were promising, this method requires daily injections and may have many off-targets. However, through our approach, we believe we can provide a more permanent and safer way to treat PWS.

The medical and developmental issues in people with PWS result from the loss of expression of the genes on the chromosome region 15q11.2-q13. These genes code for proteins that are important for neuronal development, and for non-coding RNA that is crucial for regulating the process of transcription for other genes. People typically receive a copy of these genes from each parent, and while both copies are present, the maternally inherited genes are silenced through genomic imprinting, meaning only the paternal copies are expressed. In cases where there is a deletion or mutation of the paternal copy, there is no expression of these necessary genes resulting in PWS.

However, through shRNA-mediated gene therapy, we are attempting to unsilence the maternal genes, allowing them to be expressed, which in turn would treat the root cause of PWS.  The silencing of the maternal genes is accomplished by the protein euchromatic histone lysine N-methyltransferase-2 or EHMT2/G9a/H3K9me3, which methylates the amino acid lysine at 3 sites, condensing the DNA, and therefore preventing its ability to be expressed.

​​In efforts to reverse this silencing/methylation, there has been an attempt to inhibit the EHMT2 protein using the inhibitor UNC0642. As UNC0642 is administered daily to mice with PWS, it is found that the PWS genes (SNORD116 and SNRPNs) that were turned off are expressed, and the excessive weight gain and survival rate show improvement. However, the issue with this approach is that the inhibitor for the protein must be injected daily, and there may be other off-targets involved.

 

​​What does research mean to you?

Research to me has been a way to explore and engage in novel ideas and work towards leaving my contribution to science. Through being truly passionate about the research I was doing, I found myself able to work hours on end without even noticing. I enjoyed every minute of this fellowship so much that I even continued to work in my lab through the summer.  

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Tell us about your journey​!

I knew I always wanted to get involved with research, but due to the pandemic, I wasn’t able to get any experience until the beginning of my junior year. When I heard about the Green Fellowship, I was immediately intrigued, but I felt with such little experience I was not qualified. However, my friends, who were previous Green Fellows, pushed me to apply and I am so glad and fortunate they did.

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What was your favorite part about the program? 

My favorite aspect of the program was truly experiencing what it is like to be in research full-time. With no classes, I was able to devote all my time toward learning about my research and expanding my knowledge. This allowed me to accomplish so much in such little time, further igniting my passion for research. 

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What was the biggest thing you learned from the program?

Through the program, I learned essential time management and life skills that allowed me to balance a full time job with life’s many other demands. I feel these skills I acquired are invaluable and will help me in the coming years as I work towards my career. 

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Advice for Future Green Fellows

Initially, you will feel overwhelmed and everything will be very challenging, but that is completely normal and eventually, you’ll find yourself handling everything with ease. Be prepared to work hard and know that if you were selected for this program, you certainly have what it takes. 

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