Treatment with two distinct molecules targeting the “backup” SMN2 gene resulted in higher levels of SMN — the protein lacking in spinal muscular atrophy (SMA) — and longer survival in a mouse model of type 1 disease relative to the use of a single therapy.
Notably, these benefits, which included the prevention of motor neuron loss, were observed when the combination treatment was given both before and after symptom onset. The combination also was found to be generally safe.
Given that these molecules are structurally and functionally similar to Spinraza (nusinersen) and Evrysdi (risdiplam), these findings suggest that combining such therapies may be a safe and effective approach for this patient population, even after symptoms start, the researchers said.
However, appropriately controlled clinical trials are needed to assess the safety and effectiveness of such a combo treatment in SMA patients, the team noted.
“We have … shown that this dual therapeutic approach successfully increases SMN protein and rescues motor function in symptomatic … mice,” the investigators wrote. “The promising additive effect of dual therapy observed in SMA mice must be confirmed in clinical trials with SMA patients.”
The study, “Dual SMN inducing therapies can rescue survival and motor unit function in symptomatic ∆7SMA mice,” was published in the journal Neurobiology of Disease.
Currently, three disease-modifying therapies are available for SMA: Biogen’s Spinraza (nusinersen), given directly into the spinal canal three times a year; Novartis’ Zolgensma, administered through a single into-the-vein injection; and Roche’s Evrysdi, taken daily as an oral solution.
All work to restore the levels of SMN, the protein lacking in SMA patients due to mutations in the SMN1 gene, but they do so through different mechanisms.
Zolgensma uses a harmless virus to deliver a healthy copy of the SMN1 gene to cells. Meanwhile, Spinraza and Evrysdi target, in different ways, SMN2, a “backup” gene that can partially compensate for the loss of SMN1-derived SMN.
While treatment combinations may theoretically lead to better outcomes, there is still limited data on the safety and effectiveness of such approaches.
Now, a team of researchers in the U.S. evaluated the effects of combining two mechanistically different SMN2-targeting experimental molecules in a mouse model of SMA type 1, one of the most severe forms of the disease.
Notably, each of these therapies was structurally and functionally similar to either Spinraza or Evrysdi.
The Spinraza-like therapy was an antisense oligonucleotide or ASO, a type of RNA molecule that boosts SMN production by targeting a specific region, called ISS-N1, in SMN2’s messenger RNA (mRNA). mRNA is the intermediate molecule derived from DNA that guides protein production.
The other therapy, called RG7800, is the predecessor to Evrysdi. It is a small, orally available molecule that increases the levels of SMN2-derived SMN by targeting another region, adjacent to ISS-N1, in SMN2’s mRNA.
In the study, three groups of mice were treated with each therapy or with the combined approach starting either before (2 days old), during (4 days old), or after (6 days old) symptom onset.
The ISS-N1-targeting ASO was administered directly into the animal’s cerebrospinal fluid (CSF) only once, while RG7800 was injected daily into the abdomen. The CSF is the liquid that bathes the brain and spinal cord.
Researchers evaluated SMN levels in the animal’s spinal cord eight days after the treatment’s start, and also assessed the mice’s weight and survival. The number and function of motor units, which comprise a spinal motor neuron and all the muscle fibers it innervates, also were evaluated, as were the health of neuromuscular junctions (NMJs), the site of contact between a motor neuron and a muscle cell.
The results showed that, compared with each individual therapy, the combination treatment significantly increased SMN levels — particularly when given before symptoms. In those cases, the SMN levels reached those of healthy mice.
Combining both therapies also was more effective at preventing disease-associated weight loss and at improving survival than a single treatment with RG7800 or the ASO, which was generally associated with less pronounced benefits.
Notably, while untreated mice typically died 15 days after birth, at least 80% of the mice given the combo treatment at any stage of the disease lived for more than 100 days.
Also, mice treated with both therapies after symptom onset showed similar survival to those given either individual therapy before symptom onset. When treatment was started after symptom onset, the combo was associated with an 80% increase in survival, compared with either single therapy.
Moreover, all treatment regimens were found to prevent motor unit impairment and loss in 1-month-old and 80-day-old mice, with the combo therapy providing the best outcomes and the ASO the poorest.
Similar SMA-associated NMJ function defects were observed between 1-month-old mice previously treated with either RG7800 plus ASO or RG7800 alone, suggesting that neither treatment timing nor type was “able to effectively eliminate NMJ transmission defects,” in the mouse model of SMA type 1, the researchers wrote.
The observed general superiority of RG7800 relative to the ASO may be due to its more widespread body distribution, as the ASO, when administered to the CSF, typically cannot reach tissues outside the brain and spinal cord, the team noted.
These findings highlight that combining two mechanistically distinct SMN2-targeting therapies effectively increases SMN production, prevents motor neuron loss, and extends survival in an SMA type 1 mouse model, even when given after symptom onset.
These positive outcomes suggest that the combo therapy does not result in overt toxicity and that the therapies do not compete with each other, which could potentially limit their efficacy.
As such, “it is important to perform clinical trials in SMA patients to confirm the additive effect of these SMN inducing therapies,” the team concluded.
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