Cure SMA Awards $140,000 Grant to Megerditch Kiledjian, PhD, of Rutgers

Cure SMA has awarded a $140,000 research grant to Megerditch Kiledjian, PhD, at Rutgers, The State University of New Jersey, for his project, “Novel Strategies to Increase SMN2 RNA.”

Because of a genetic mutation in the SMN1 gene, individuals with SMA don’t produce survival motor neuron protein (SMN protein) at high enough levels. All individuals with SMA have at least one copy of SMN2, the SMA “backup gene,” which produces a small amount of functional SMN protein.

Researchers believe that prompting SMN2 to make more protein could be an effective way to treat SMA. Dr. Kiledjian and his team have identified a previously unknown protein variant that could lead to increases in SMN2 mRNA and SMN protein. Understanding the basis for this could help better understand how the SMN gene is turned on and off and identify new targets for SMA drug development.

Meet. Dr. Kiledjian

Who are you?

I received my Ph.D. in Molecular Biology at the University of Pennsylvania and am currently Distinguished Professor and Chair of Cell Biology and Neuroscience at Rutgers University. I have a long standing interest in questions related to RNA biology, in particular how a certain type of protein, called a mRNA decapping enzymes, regulates whether a gene is turned on and off. I have an interest in how this process is affected in human disease with a recent emphasis on SMA.

How did you first become involved with SMA

My entry into SMA research was serendipitous and facilitated by Cure SMA’s efforts to identify SMA drug candidates. The scavenger decapping protein DcpS had been discovered in my lab. A possible role of DcpS in SMA was the conduit for our entry into the field almost eight years ago and since then we have pursued mechanisms by which SMN protein can be increased in SMA patient cells.

What is your current role in SMA research?

Pharmacological intervention to up regulate the SMA modifier gene, SMN2, is a promising avenue for therapeutic intervention in SMA pathogenesis. We have identified a variant form of one protein that can significantly elevate full length (fl)-SMN2 steady state mRNA and SMN protein in SMA patient cells. Deciphering the molecular basis by which the variant protein functions to elevate SMN2 mRNA will provide a foundation for potential future therapeutic intervention for SMA.

What do you hope to learn from this research project?

Our overall objective is to increase levels of SMN2 mRNA and SMN protein in SMA patient cells as a means to ameliorate SMA. Towards this end, we have identified a variant form of a known protein that when expressed in cells at detectable levels, leads to increased SMN2 mRNA and protein. Our goal is to understand how this variant protein increases SMN2 levels and implement this information for therapeutics development.

How will this project work?

Having identified a previously unknown way of increasing SMN2 mRNA in SMA patient cells, we will uncover how this occurs and how we can utilize this information to treat SMA. We will be using type I SMA cell lines to determine the molecular mechanism underlying this new way of increasing SMN protein levels in patient cells. We will also devise novel therapeutic strategy in cells with the goal to ultimately treat SMA.

What is the significance of your study?

SMA is a debilitating disease characterized by the loss of spinal motor neurons due to the absence of the SMN1 gene. Unfortunately, there are no current effective treatments for SMA, although increased expression of the SMN2 gene can reduce the severity of SMA. Therefore therapeutic approaches to increase SMN2 expression would be beneficial in SMA patients. Our objective is to decipher the molecular mechanism underlying this new mode of SMN2 upregulation and implement strategies to utilize in therapeutic intervention for SMA patients.

Basic Research Funding

This grant to Dr. Kiledjian is part of $890,000 in new basic research funding that we’re currently announcing.

Basic research is the first step in our comprehensive research model. We fund basic research to investigate the biology and cause of SMA, in order to identify the most effective strategies for drug discovery. We also use this funding to develop tools that facilitate SMA research.

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