Each year, Cure SMA invites scientists from around the world to submit funding proposals for basic research projects that address specific unanswered questions in SMA biology. Our Scientific Advisory Board ranks the submitted proposals on both their scientific merit and relevance to the Cure SMA research priorities. This year, Cure SMA’s top basic research priorities include:

  • Learning about the roles the survival motor neuron (SMN) protein plays throughout the body.
  • Understanding the details of how SMN-dependent therapies work.
  • Finding treatment targets other than SMN.
  • Combining SMN-dependent therapies and other treatments to achieve the best possible outcomes.

In 2022, Cure SMA awarded a total of $525,000 to five scientists to explore some of these questions.

Alberto Kornblihtt, PhD, at the Universidad de Buenos Aires in Argentina has been awarded $150,000 for his research project, “Epigenetics in SMN2 E7 Alternative Splicing.”

Meet Dr. Kornblihtt

Tell us about yourself.

I was born in 1954 in Buenos Aires, Argentina. I graduated as a biologist (1977) from the Facultad de Ciencias Exactas y Naturales of the University of Buenos Aires (FCEN-UBA). I obtained my PhD in Biochemistry in 1980 at the Campomar Foundation. I did my postdoctoral research (1981-1984) at the Sir William Dunn School of Pathology in Oxford, UK, where I cloned the human fibronectin gene and discovered that it is alternatively spliced.

I am Professor at the Department of Physiology, Molecular, and Cell Biology at the FCEN-UBA. I am also Senior Investigator of the National Research Council of Argentina at the Institute of Physiology, Molecular Biology, and Neurosciences. I am a Foreign Member of the National Academy of Sciences of the USA, the French Academy of Sciences, and the European Molecular Biology Organization.

How did you first become involved with SMA research?

As an expert in alternative splicing, I was aware that treatment for SMA could be achieved through the control of alternative splicing of the SMN2 gene. However, it wasn’t until 2015 that I was approached by the Families of SMA, Argentina (FAME). They encouraged me to start a new project in which my lab in Buenos Aires would join efforts with Dr. Adrian Krainer’s lab in Cold Spring Harbor, New York, to test whether the use of the molecular tools we have developed in our lab could improve the effectiveness of already approved treatments such as Spinraza (nusinersen).

What is your current role in SMA research?

My lab works on the regulation of alternative mRNA splicing, explaining how a single gene generates multiple proteins. We found that the cellular mechanism that copies genes into RNA (known as transcription) is key to regulating alternative splicing. We also found that changes in chromatin structure are crucial for alternative splicing decisions. Based on this knowledge, we are exploring strategies to improve the efficacy of Spinraza with drugs that, by affecting chromatin structure, could be used in a combined therapy for SMA.

What are the project goals?

The goal of this project is to understand how the epigenetics of the SMN2 gene interact with an antisense oligonucleotide (ASO1) that resembles Spinraza (nusinersen). Epigenetics are factors that affect how much protein is produced from a gene without changing the genetic code itself. These factors include things like chemical changes to the DNA or other molecules binding to the gene.

Spinal muscular atrophy (SMA) is caused by recessive mutations of the survival motor neuron 1 (SMN1) gene. These mutations result in reduced levels of the survival motor neuron (SMN) protein, which cause motor neuron death and muscle atrophy. In addition to the SMN1 gene, everyone has at least one copy of a second gene, SMN2. SMN2 also encodes the SMN protein and can act as a “back-up” gene to the mutated SMN1 gene. However, because of a small difference in the SMN2 gene sequence, the majority of protein that is made from SMN2 is shortened or “truncated” and doesn’t function very well. Truncation of the SMN2 protein occurs when the SMN2 gene is copied or “transcribed” into mRNA, and a portion of the gene known as “exon 7” is spliced out of the mRNA sequence.

The Kornblihtt lab has identified epigenetic factors that affect the splicing of SMN2 mRNA and the effectiveness of AS01. Like Spinraza, AS01 binds to SMN2 mRNA to prevent the splicing of exon 7 and increase the amount of full-length SMN protein. This project is designed to learn more about how the interplay between AS01, epigenetic factors, and the SMN2 gene affects the production of full-length SMN protein.

What will the results tell us?

One way to treat SMA is to increase the amount of full-length SMN protein in affected individuals by reducing SMN2 splicing. Therefore, epigenetic factors that affect SMN2 mRNA splicing could be useful targets for new SMA treatments. These new treatments may be used in combination with existing therapies like ASOs to achieve the best possible patient outcomes.

*Thank you to the Dhont Family Foundation for their support of this important basic research project.