An increased amount of SMN protein — crucial to the survival of motor neurons — in the blood could reflect similar increases in the brain, spinal cord, and peripheral tissues after spinal muscular atrophy (SMA) treatment with the oral therapy risdiplam, researchers say.
They believe these findings in animal models suggest that non-invasive measurements in the blood could indicate changes in SMN protein levels in the central nervous system (CNS).
The research, “Risdiplam distributes and increases SMN protein in both the central nervous system and peripheral organs,” appeared in the journal Pharmacology Research & Perspectives.
All genetic information contained within genes (DNA) is ultimately translated into proteins. However, several complex steps exist before a protein can be produced. DNA is transformed into pre-messenger RNA (pre-mRNA), which is then processed to originate a mature mRNA molecule. This process is called RNA splicing. Once mRNA molecules are produced, a process called translation begins, which gives rise to proteins.
During splicing, introns (the part of the pre-mRNA that does not code for proteins) are removed and exons (the part that does) are joined together. This phenomenon allows for a single gene to give rise to many different proteins.
Risdiplam (formerly RG7916) — developed by Roche in a collaboration with PTC Therapeutics and the SMA Foundation — changes the way pre-mRNA is spliced so that full-length mRNA and higher levels of functional SMN protein are produced from SMN2.
Although with a different molecular target, Spinraza (nusinersen, by Biogen) also works by increasing the amount of functional SMN protein by modifying SMN2 mRNA splicing. Its approval for pediatric and adult SMA patients validated the mechanism of action and effectiveness of this type of therapy, researchers noted.
While progressive loss of specialized cells called motor neurons is the hallmark of SMA — leading to muscle atrophy, or shrinkage, and weakness — the disease has been increasingly regarded as one that also affects other tissues and cell types. As such, effective treatment may require body‐wide correction of SMN protein levels.
Risdiplam is an orally administered small molecule that specifically targets exon 7 of SMN2 in both peripheral organs and the central nervous system — the brain and spinal cord. Compared to other SMN2 splicing modifiers, risdiplam showed greater efficacy and safety in prior studies.
Using cell cultures and animal models of SMA, researchers evaluated the extent of central and peripheral tissue distribution of risdiplam as well as biomarker levels following its administration. According to the team, which included investigators from Roche, PTC and the SMA Foundation, this provides the basis to estimate changes in functional SMN protein level in target tissues via blood sampling.
The study showed that single or repeat daily administration of risdiplam for up to 39 weeks led to similar total levels in the plasma, brain, and muscle of mice, rats, and monkeys. Levels in plasma strongly correlated with the compound’s amount in tissues over a broad range of concentrations. Analysis in different brain areas of monkeys further evidenced similar distribution of risdiplam. Also in monkeys, levels of risdiplam in the cerebrospinal fluid (a liquid surrounding the brain and spinal cord) reflected free compound concentration in plasma.
As for the therapy’s elimination from the body, experiments in rats and mice showed that risdiplam levels in plasma and the brain decreased in parallel. Orally administered, radioactive-labeled risdiplam reached its peak concentration at two hours in most rat tissues, with higher tissue/plasma ratios in the spleen, liver, lung, bone marrow and kidney cortex, all of which are known to be affected in SMA.
Experiments in mice showed dose-dependent increases in SMN protein in the brain and muscle upon once-daily dosing with risdiplam. The potential medication extended the survival of mice treated over 219 days, while improving their muscle function and increasing body weight.
“These in vitro and in vivo preclinical data strongly suggest that functional SMN protein increases seen in patients’ blood following risdiplam treatment should reflect similar increases in functional SMN protein in the CNS, muscle, and other peripheral tissues,” researchers stated.
Risdiplam is being investigated in multiple clinical trials, including the Phase 2/3 trials FIREFISH, in type 1 SMA (NCT02913482), and SUNFISH, in types 2 and 3 (NCT02908685). Both studies showed that a significant number of patients were able to achieve developmental milestones, while also showing relevant motor function improvements.
The milestones included babies being able to reach for things, lift their heads, sit without support and preserve their swallowing and breathing functions.
The treatment candidate is also being studied in the Phase 2 JEWELFISH trial in type 2/3 infants to adults (NCT03032172), currently enrolling patients. A further trial in pre-symptomatic type 1 infants, called RAINBOWFISH, is yet to open.