Cell-released particles may help track SMA progression, Spinraza response
Extracellular vesicle levels dropped steadily after patients began treatment: Study
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- Extracellular vesicles (EVs) are potential biomarkers for SMA progression and Spinraza treatment response.
- Untreated SMA patients show elevated EV levels, which decrease with Spinraza therapy.
- Specific EV-associated proteins also change, offering new ways to monitor treatment effectiveness.
Blood levels of tiny cell-released particles called extracellular vesicles (EVs) could serve as a tool to track disease progression and treatment response in people with spinal muscular atrophy (SMA), a small study suggests.
Researchers discovered that these microscopic particles, which carry cargo between cells, were elevated in untreated SMA patients but dropped steadily after patients began treatment with Spinraza (nusinersen). The study also identified several specific proteins carried by these vesicles that shift during treatment, offering a potential new way for doctors to measure how well a therapy is working.
If effective, these biomarkers could help doctors make more personalized treatment choices as more SMA therapies are approved, or be “used as standard of care to more accurately monitor the slow progression of the disease,” researchers wrote.
The study, “Extracellular vesicles as biomarkers of disease progression and therapeutic response in patients with spinal muscular atrophy,” was published in Molecular Therapy Advances.
The search for better monitoring tools
SMA is a neuromuscular disease chiefly caused by mutations in the SMN1 gene that lead to a deficiency of the survival motor neuron protein (SMN). This results in the progressive loss of motor neurons, the nerve cells that control movement, and symptoms such as muscle weakness and wasting.
While there are several disease-modifying treatments available and more in clinical development for SMA, “there is an unmet need for biomarkers that can quickly and accurately evaluate a patient’s response to therapy,” the scientists wrote. Such information may help guide therapeutic decisions, define drug dosage, or determine whether patients are not responding and should switch to a different treatment, they added.
In the study, a research team in Canada assessed whether the levels of extracellular vesicles, which are cell membrane-bound nanoparticles released from all cell types in all body fluids, could be used as biomarkers of response to Spinraza. Previous studies from the same team supported this theory, showing that EV levels were increased both in SMA models and in a person with the disease.
To test this further, they analyzed data from four women with SMA type 3, ages 38 to 63 years, who were receiving Biogen‘s Spinraza for up to nearly 4.5 years. The study also analyzed samples from healthy people who served as controls.
Before starting Spinraza, patients showed a trend toward higher EV levels in both blood and cerebrospinal fluid (CSF), the liquid surrounding the brain and spinal cord, compared with healthy controls. However, the average physical size of the vesicles was similar between the two groups.
Next, the researchers analyzed EV levels before and after starting Spinraza, using samples collected immediately before each treatment dose. Following the start of therapy, all patients showed a progressive decline in their blood EV levels.
After adjusting for each patient’s baseline EV levels before treatment, the results showed a significant association between EV levels and Spinraza dose. This indicated a progressive decrease in blood-derived nanoparticle concentration throughout therapy. In contrast, CSF samples showed little variation in EV levels before and after treatment, with only a very modest decrease during therapy.
Tracking specific protein shifts during treatment
A proteomic analysis was then conducted to evaluate the blood levels of proteins commonly associated with EVs. Overall, it identified 72 proteins or protein pairs, seven of which were strongly associated with blood EV levels: ADAM10, CD59, CD82, glypican-2, syndecan-3, and the integrins alpha-E-beta7 and alpha-V-beta1.
Additionally, among the seven proteins whose levels were significantly different between patients and controls before treatment, two were significantly elevated in the SMA group (CD47 and CD81), while the remaining five were reduced in the patient group.
Four of these proteins were no longer different from controls after treatment. Within the SMA group, integrin alpha-E-beta7 was the only one of these proteins whose levels were significantly decreased after nine doses of Spinraza. During treatment, 21 proteins or protein pairs across several categories showed significant changes in their levels, representing potential markers of treatment response in SMA patients.
“These findings suggest that nanoparticles and several EV-associated marker proteins hold promise as potential biomarkers for disease state and treatment response in individuals undergoing [Spinraza] therapy,” the researchers wrote.
Although this study focused on patients with SMA type 3, which is a milder form of the disease, the researchers noted that future studies must determine whether these markers are also altered in more severe SMA types or in response to other disease-modifying therapies.
