SRP-5051 is an experimental RNA-targeted treatment being developed by Sarepta Therapeutics for Duchenne muscular dystrophy (DMD) patients who have mutations amenable to exon 51 skipping — approximately 13% of all people with DMD.
How SRP-5051 works
DMD is caused by mutations in the DMD gene, which codes for a protein called dystrophin that normally acts like a shock-absorber to cushion muscle cells, preventing wear and tear during movement. Protein-coding genes like DMD are composed of exons — the regions of DNA that actually code for the protein — which are interspersed with non-coding regions called introns. When a gene is “read,” the genetic code, including exons and introns, is copied into a temporary molecule called messenger RNA or mRNA. The mRNA is then edited to remove all the introns, with exons spliced together to form the mature genetic sequence that can then be “read” to make a protein.
When genetic code is “read,” the nucleotides (“letters” of code) are grouped into clusters called codons, somewhat analogous to how letters are grouped into words in a sentence. Some DMD-causing mutations can result in a frameshift, where all the subsequent codons get out of alignment — imagine removing the last letter from every word in a sentence, and adding it to the start of the next word. The result is basically that only the first portion of the protein gets made, resulting in an unstable product that is quickly degraded in the cell.
In patients with specific mutations, skipping the 51st exon of the DMD gene can “fix” the frameshift, allowing the cell to correctly “read” the code downstream of the mutation. By skipping exon 51, the cell can make a shortened, but still functional, version of dystrophin.
SRP-5051 contains an antisense oligonucleotide (lab-made DNA molecules) that prompts exon 51 to be removed from the DMD mRNA during splicing, effectively skipping the exon. SRP-5051 is designed to work similarly to Exondys 51 (eteplirsen), an older exon 51-skipping therapy developed by Sarepta. SRP-5051 is a next-generation version of the older therapy that has been modified by adding a peptide (a small chain of amino acids, the building blocks of proteins) that allows the therapy to more effectively get inside of cells.
SRP-5051 in clinical trials
A Phase 1 clinical trial (NCT03375255) recruited 15 DMD patients, 12 and older, with mutations amenable to exon 51 skipping at seven sites in the U.S. and one in Canada. Participants were given one of five escalating doses of SRP-5051 given via intravenous (IV) infusion, and their blood was sampled at 15 minutes, 30 minutes, and 1, 2, 4, 8, and 12 hours following infusion to evaluate the therapy’s pharmacological properties. Safety-related outcomes also were recorded for up to 14 weeks post-treatment. The study finished in August 2019, but results have not yet been released.
Sarepta is currently sponsoring an ongoing two-part Phase 2 clinical trial called MOMENTUM (NCT04004065) to further explore the efficacy, safety, and pharmacological properties of SRP-5051. In Part A of the study, participants were given monthly IV infusions of SRP-5051, starting at a dose of 4 mg/kg and increasing to 40 mg/kg, over 12 weeks.
Results from Part A indicated that SRP-5051 was generally well-tolerated at all studied doses, with no serious adverse effects (side effects) reported. The treatment also consistently increased exon-skipping and dystrophin protein levels. Comparisons against results from earlier studies that tested Exondys 51 indicated that SRP-5051, at a dose of 30 mg/kg monthly for three months, could increase dystrophin levels by eight times more than Exondys 51 given weekly for six months.
In Part B of the study, participants will be given infusions of SRP-5051 every four weeks, at doses selected based on the results from Part A, for up to two years. The main goal of this portion of the study is to determine the effect of treatment on dystrophin levels after 28 weeks (about half a year). Participants in Part B also will be given magnesium supplements, because reversible low magnesium levels have been reported in participants given the therapy.
Part B of the study is currently enrolling males with DMD, ages 7 to 21, who have mutations amenable to exon 51 skipping at sites in the U.S., Canada, and Europe. Patients who completed Part A can transition to Part B.
Last updated: Feb. 17, 2022, by Marisa Wexler MS
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