Raising SMN protein levels may be helpful early step in SMA treatment
A combination of a ready-to-use SMN protein and an experimental treatment targeting the SMN2 gene, which works in a similar way to Spinraza (nusinersen), eased abnormalities in motor neurons derived from a spinal muscle atrophy (SMA) patient, researchers report.
The addition of the protein, raising SMN protein levels (expression), in combination with an SMN2-targeting therapy was more effective than either of those approaches alone, the team, which created this full-length protein, noted.
“These results provide compelling proof-of-principle evidence of the therapeutic potential of our [ready-to-use] protein as an add-on to the existing therapies,” the researchers wrote.
The work, “Recombinant SMN protein synergizes with spinal muscular atrophy therapy to counteract pathological motor neuron phenotypes,” was published as a letter in Translational Neurodegeneration by a research team in Italy.
‘Additional approaches’ needed to make current SMA therapies more effective
A rare genetic condition marked by disease symptoms of progressive muscle weakness and wasting, SMA is caused by mutations in both copies of the SMN1 gene. As a result, little to no SMN protein is made, leading to a loss of motor neurons — the specialized nerve cells that control voluntary movement.
Spinraza, the first approved disease-modifying treatment, is an antisense oligonucleotide or ASO — a type of RNA-based molecule. The therapy is designed to increase SMN protein levels by binding to SMN2’s messenger RNA molecule (mRNA, essential for protein production) and correcting its splicing, a process that enables a single gene to produce many different proteins.
Without targeted treatment, SMN2 — a “backup” gene for SMN1 in people — gives rise to a shorter, less stable, and poorly working protein.
Existing disease-modifying SMA therapies — Spinraza, Evrysdi (risdiplam), and the gene therapy Zolgensma (onasemnogene abeparvovec-xioi) — can provide significant motor and respiratory benefits to patients. However, response to treatment is variable, with these therapies seen to be most effective when administered early in life.
“An important limitation” for Spinraza and Evrysdi, both SMN2 splicing modifiers, is that they cannot rapidly induce high SMN protein production, the scientists noted. The amount of available SMN2 mRNA also can be limited in patients, especially those with SMA type 1, a common and severe disease form.
“These observations suggest that existing treatments are still not a cure, highlighting the need for the development of additional approaches to improve the efficacy of these available therapies,” the researchers wrote.
Ready-to-use protein tested in neurons derived from SMA patient and carrier
These scientists developed a novel therapy, called TAT-flSMN, that delivers a full-length, ready-to-use human SMN protein. They went through various lab tests of this protein, including in motor neurons derived from induced pluripotent stem cells of an SMA type 2 patient and a healthy, related SMA carrier (one faulty SMN1 gene copy). These stem cells are notable because they can be programmed to develop into any type of cell in the body; in this study, they matured as motor neurons.
Results showed that the neurites (nerve cell projections) of motor neurons from the SMA patient were shorter and more susceptible to programmed cell death than those derived from the carrier, who served as a control.
The defects eased when the patient’s motor neurons received increasing doses of TAT-flSMN, the scientists reported. Longer neurites and lesser nerve cell death also were observed in motor neurons treated with PMO25. PMO25 is an experimental ASO that targets the SMN2 gene, working similarly to Spinraza to boost the production of a working SMN protein.
TAT-flSMN and PMO25, used in combination, more effectively lessened SMA-related changes in motor neurons than either therapy alone, “suggesting that a timely SMN boosting can greatly ameliorate pathological [disease-related] motor neuronal phenotypes [characteristics] in SMA,” the researchers wrote.
“We envision that the clinical management of SMA will improve with more refined strategies to raise SMN expression, such as TAT-flSMN, but also by associating them with nutritional and rehabilitation programs in an all-encompassing patient care plan,” they concluded.
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