Gene Silencing

Robert H. Brown, Jr, DPhil, MD, University of Massachusetts

We have had some significant forward momentum in our HSAN1 work. Havisha Karnam has generated a series of chemically modified anti-sense oligonucleotides (small pieces of DNA or RNA that block the production of proteins in the cell) that very clearly suppress expression of SPTLC1 in vitro (in a culture dish). We now have assays pending to ascertain if, as we predict, this also silences expression of the deoxysphingoid bases (backbone of sphingolipids).

In a parallel project, we have generated microRNA that silence expression of the SPTLC1 gene in cells, also in vitro. We are now almost completed packaging this in an adenoassociated virus (AAV) for testing in the HSAN1 mice. We hope to be infusing the mice with the AAV containing the microRNA to silence SPT by the end of June. This has taken longer to get up and running than we anticipated but should nonetheless be accomplished shortly. This is the work of Gaby Toro and Nick Wightman.

A post-doc in the lab, who works on microRNA biology, formerly studied aspects of serine palmitoyltransferase inhibition, ceramide levels and pathology in Alzheimer’s Disease. This individual, Hirosha Geekiyanage, has worked with our

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L-serine Study Results

Vera Fridman, Peter Novak, William David, Diane McKenna-Yasek, Kailey Walsh, Anne Louise Oaklander, Robert Brown, Thorsten Hornmann, and Florian Eichler.

The L-serine study supported by the Deater Foundation was presented at last year’s Deater Foundation International Symposium and at the American Academy of Neurology’s 2017 Annual meeting. The paper has been submitted for publication.

The study sought to evaluate the safety and efficacy of L-serine in patients with HSAN1. Eighteen patients with HSAN1 and prominent sensory loss, foot ulcers, or shooting pains took part. Half received L-serine and half received placebo for a year. The study was “double-blind”, so the researchers did not know which participants received the supplement and which received the placebo. Dr. Eichler at Massachusetts General Hospital and Dr. Brown at the University of Massachusetts collaborated with other researchers for the study. After 48 weeks all participants took L-serine for an additional year.  16 subjects completed the study. There were no serious adverse effects related to L-serine. Testing showed improvement in the L-serine group vs. placebo at one year and improvement in all participants at the end of the study. The study concluded that L-serine is a safe and potentially efficacious treatment for HSAN1.

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