Researchers have identified outcome measures and biomarkers of disease progression that may allow them to differentiate between types of spinal muscular atrophy (SMA) and could be beneficial in evaluating current and future therapeutic approaches.
Their findings were published in the study, “Prospective and longitudinal natural history study of patients with Type 2 and 3 spinal muscular atrophy: Baseline data NatHis-SMA study,” in PLOS One.
Spinraza (nusinersen) has been approved in both the U.S. and EU for the treatment of all SMA types, and several therapeutic strategies are currently under investigation.
As more treatments become available, the number of untreated patients is expected to decline, and the need to define the natural history of the disease and identify the right association of responsive outcome measures and biomarkers for individual patient follow-up increases.
In this study, researchers identified prognostic variables and biomarkers of SMA progression by using a broad range of carefully chosen, standardized evaluations and assessments in patients participating in the NatHis-SMA study (NCT02391831) — a prospective, longitudinal, and interventional study of the natural history of patients with SMA types 2 and 3.
The objective of the trial was to characterize the disease course over two years and identify prognostic variables of the disease and biomarkers of SMA progression, as well as to determine the best outcome measures for further therapeutic approaches.
Researchers then analyzed whether these outcome measures and biomarkers could “define the different levels of the disease phenotype (muscle atrophy and its subsequent muscle weakness)” and whether they could differentiate “patients with various levels of disease severity and correlate with the motor function,” according to the study.
This multicenter study involved 81 SMA patients, from 2-30 years old, including 53 with SMA type 2 and 28 with SMA type 3. Patients were assessed using established outcome measures at the beginning of the study and then every six months. Over the course of the study, motor development, cognition, respiratory function, and level of care required were among the variables assessed, using established tests such as the motor function measure (MFM).
Pulmonary function and strength tests, upper limb function and abilities, compound muscle action potentials and muscle imaging could discriminate between non-sitter patients with SMA Type 2, sitter patients with SMA Type 2, non-ambulant patients with SMA Type 3, and ambulant patients. Furthermore, all assessments used correlated with MFM scores.
“… [O]ur results confirmed the psychomotor developmental delay as well as the higher and earlier functional degradation in the more affected patients with SMA Type 2. This included a higher incidence of scoliosis in patients with SMA Type 2 than in Type 3 and a higher incidence of arthrodesis [surgical fusion of two joints in the body] in the non-sitter patients than in sitter individuals,” the researchers wrote.
All patients received physiotherapy; however, SMA type 2 sitter patients reported a greater frequency of sessions than ambulant patients.
“… [T]he extensive panel of supportive devices used for nutrition and respiratory management as well as the frequent orthotic use reflects the adapting strategies as standard of care for the wide-range of phenotypes,” the researchers said.
Upper extremity strength and function assessments were also performed, using devices that measured grip and pinch strength, the capacity to repeatedly flex and extend the hands and fingers, upper extremity workspace volume and trunk control (using a gaming interface), and monitored linear and rotational arm movements and velocity in the home.
These tests were able to distinguish SMA type 2 patients from those with type 3 and strongly correlated with MFM results. They also revealed varying levels of strength and function within the non-ambulant SMA type 3 population, yet these differences were indiscernible from the MFM score alone.
“Altogether, this demonstrates that combining these tests with MFM optimizes motor function assessment, irrespective of the disease type or ambulant status,” the researchers wrote.
In terms of pulmonary function, SMA type 2 patients had the most impaired lung function, whereas ambulant patients had close to normal values. None of the measured parameters significantly differed between non-ambulant SMA type 3 patients and ambulant patients; however, this could be due to the small sample sizes, the authors said.
Genetic analysis revealed, as expected, that most SMA type 2 patients had two to three SMN2 gene copies, whereas most type 3 patients have three or four copies. However, the broad clinical variation among patients with three gene copies suggests that other factors also account for clinical severity.
Neither SMN2 nor SMND7 (another form of the SMN gene) levels were related to clinical severity nor with motor function. Importantly, SMN protein expression was not correlated with MFM scores and greatly overlapped between SMA types, “with high variability irrespective of the sitter or ambulant statuses,” according to the study.
None of the patients examined had cognitive impairments, confirming that SMA is not an obstacle to education.
“The objective of the longitudinal data analysis will be to identify if these outcome measures can capture even more discrete changes over time and show possible differences in disease progression between the three functional patient groups,” the researchers said.
“As the untreated patient population decreases, having reliable and valid multi-site data will be imperative for recruitment in clinical trials,” they added.