In the United Kingdom, the SMA Trust is working to promote research and development of new treatments for spinal muscular atrophy (SMA). By providing funding and bringing together researchers, patients, healthcare professionals, and pharmaceutical industry representatives, it strives to accelerate research that might bring solutions to patients.
In a recently published article, “The SMA Trust: the role of a disease-focused research charity in developing treatments for SMA,” the nonprofit organization reviews ongoing research efforts it funded. The review was published in the journal Gene Therapy.
Despite the recent approval of Spinraza (nusinersen), a large need for SMA treatment development persists, the SMA Trust maintains. The trust has put plenty of efforts into making the drug readily available to UK families.
“Success relies on cooperation and collaboration,” the SMA Trust wrote in its review. “Clinicians, patient groups, the pharmaceutical industry, charities, academic researchers, the biotechnology industry and regulators, all have a key role in meeting this huge need.”
Relying on SMN2
Spinraza is a drug that increases the production of SMN protein from the SMN2 gene. This is done with the help of so-called splice-switching oligonucleotides. Currently, the drug is administered as intrathecal injections into the spinal canal.
But some researchers think it is possible to design splice-switching oligonucleotides that can be given in other ways. The SMA Trust has funded a study that explores this possibility.
Researchers at the University of Oxford have shown that if you link the oligonucleotide to a small protein part, it is possible to deliver it into the bloodstream. The drug then enters the brain, and mouse studies have shown that the compound appears more potent than an oligonucleotide alone.
The Trust has also funded gene therapy research, aiming to replace the faulty SMN gene. It has supported research to improve how the treatment is administered, studies to optimize the viral system, which delivers the treatment, and tested it in large animals — studies that are needed before a therapy can be tested in patients.
At the University of Sheffield in the U.K., researchers are working on the development of Resagen — an SMA gene therapy that is currently in preclinical development.
SMA Trust-funded research shows that these efforts are needed in an early disease stage. The SMN protein is needed during certain events in the nerve-muscle development. With this knowledge in hand, researchers at the University of London are working to understand if it might be possible to develop a gene transfer treatment during pregnancy. The research, supported by the trust, has so far shown promise.
SMN is not the only answer
While SMN is crucial during early development, research indicates that molecular events downstream of the protein can be targeted to relieve SMA. This might be particularly important if treatment is given later than the optimal time window during development.
Together with SMA Europe, the trust is supporting University of Sheffield researchers who are investigating whether blocking a factor called PTEN might be beneficial in SMA. Mouse experiments suggest that removing the molecule prevents the death of motor neurons and allowed animals to survive longer.
Meanwhile, researchers in Edinburgh, Scotland, have homed in on the so-called ubiquitin pathway. When SMN is lacking, the pathway does not work properly. But when scientists increased the levels of a key ubiquitination enzyme, it prevented motor neuron disease and improved movement in SMA zebrafish models.
In SMA mice, boosting the enzyme — called UBA1 — resulted in a number of benefits, including less weight loss, better movement capacity, less organ and neuromuscular damage, and better survival.
Organ damage in SMA
Children born with very severe SMA might have damage to other organs beyond the neuromuscular system. Researchers agree that while motor neurons are most vulnerable to the lack of SMN protein, other cells also suffer consequences when levels drop to extremely low levels.
Much research supporting this theory comes from animal studies, but the trust has also supported human studies.
Such studies indicated that SMN is needed for the normal development of the spleen, liver, and blood vessels.
“Nusinersen [Spinraza] is a major milestone, but only the beginning of a new era of SMA therapy,” the SMA Trust said in its review. “The SMA Trust will, therefore, continue to contribute to SMA Europe’s research funding activities.”