According to scientists, new research on ALS may shed light on the mechanisms underlying spinal muscular atrophy. Two RNA binding proteins, TDP-43 and hnRNP A1, are abnormal in certain cases of ALS. This leads to their accumulation in ALS patients' nerve cells associated with movement. As the name suggests, RNA binding proteins have the capacity to bind with RNA molecules, limiting their ability to become proteins. University of Montreal researchers wanted to understand what happened to movement nerve cells when they removed TDP-43 from the cells' nucleus. Depleting the binding protein TDP-43 led to changes in the processing, or splicing, of messenger RNA in the cell. Because TDP-43 binds with RNA, and can change how it is spliced, depleting it in the cell nucleus led to alterations to another RNA binding protein, hnRNP A1. This protein can get spliced into two variations, both regulated by TDP-43. Changes in hnRNP A1 messenger RNA also resulted in protein aggregation and were toxic to cells. Importantly, hnRNP A1 controls splicing of the SMN gene, the underlying cause of SMA. Researchers don’t know how the hnRNP A1-triggered SMN splice variation affects the function of the SMN gene. But they noted that Spinraza, a therapy recently approved for SMA, targets the hnRNP A1 protein's splicing of the gene. Spinraza was derived from this same type of research.
Articles by Patricia Inacio, PhD
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Envisagenics has raised a total of $2.35 million to continue working to discover RNA-based therapies for diseases linked to RNA splicing errors, such as spinal muscular atrophy. The company uses an innovative platform that couples RNA splicing analysis with artificial intelligence. The biotechnology company's drug discovery platform, called SpliceCore, aims to develop therapeutics that correct splicing errors in RNA — the molecule that, along with DNA, gives the instructions to make all the proteins required for our cells to function. Errors in RNA splicing — a natural process cells use to generate a variety of RNA molecules by simply arranging the building blocks that compose the RNA molecule in different ways — are the cause of more than 300 genetic diseases, including SMA. With RNA splicing analysis, researchers are able to analyze millions of RNA sequence codings and identify RNA splicing errors. The most plausible and likely targets for treatments, after being validated in experiments using patients’ data, are then identified by artificial intelligence. With a target identified, researchers can then design a tailored drug and investigate its action, or how well it might work, using the SpliceCore's modular platform. The money was raised in what is called seed capital round, in which an investor funds a company in exchange for an equity stake in it.
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The gene therapy developer AveXis will start a pivotal clinical trial of AVXS-101 for people with SMA type 1. U.S. Food and Drug Administration officials agreed to the trial after AveXis submitted information the agency requested on the drug's manufacturing process and other matters. The request was made at a meeting the sides held in May. AveXis did not say in its announcement whether the pivotal trial would be a Phase 2 or Phase 3 study. The company has completed a Phase 1 trial of AVXS-101. Most pivotal trials are Phase 3, but occasionally they can be Phase 2. . AVXS-101 is a proprietary gene therapy for SMA types 1 and 2. Designed to deliver a functional copy of an SMN gene to motor neuron cells, it aims to prevent additional muscle degeneration. The pivotal trial in SMA type 1 – called STR1VE – will be an open-label, single-arm, single-dose, multi-center study. It will evaluate the safety and effectiveness of a one-time dose of AVXS-101 delivered intravenously or directly into the blood circulation. Researchers will administer a dose established in a Phase 1 trial that they confirmed with new analytical methods that the FDA reviewed. The dose was also extensively tested in a mouse model of SMA. AveXis expects to enroll in the trial at least 15 patients with SMA Type 1 younger than six months of age. One of the trial's primary objectives will be to see if AVXS-101 can help an 18-month-old infant sit without help for at least 30 seconds. Another primary objective will be to help an infant achieve event-free survival at 14 months of age, and to see whether AVXS-101 helps patients thrive — that is, not requiring feeding support, tolerate thin liquids and maintain weight. Another secondary objective will be to help infants get off ventilator support at 18 months of age. Updates of these studies are expected at the end of the year.