One and done
Because meningoradiculitis occurred in the first patient, immunosuppressive drugs were administered to the second patient.
The functional status and vital capacity of the second patient were relatively stable during a 60-week period, a course that could be typical of the slow disease progression in patients with this SOD1 genotype.
As with the first patient, this man did not experience a substantial change in SOD1 protein levels in CSF, and he did not show clinical improvement.
The main advantage of a viral gene therapy is that it could be a one-time treatment; ideally, it could be used to replace a single missing gene in conditions such as cystic fibrosis. “The hope is that the virus will drop off the gene modulator or the gene itself of interest, depending on the disease, and that the gene will be there more or less indefinitely,” said Dr. Brown. “So the cliché is, ‘one and done’—if all goes well.”
This small study illustrates that gene therapy safely “turns off genes and that the extent of suppression of genes can be significant,” said Dr. Brown.
Most SOD1 mutations could be treated with this microRNA viral vector, he added. More than 180 such mutations have been identified in ALS.
Additional studies are now needed to determine the results of this method in a larger number of patients who have ALS with SOD1 mutations, the investigators wrote.
Within reach
Both studies are encouraging in that they show that a precision-medicine approach to ALS associated with single mutated genes “may be within reach,” said Dr. Hardiman.
She noted that gene therapies have been used successfully in other motor neuron conditions. For example, an ASO and a viral vector have “very significant efficacy” in a form of spinal muscular atrophy that occurs in infants. “So the underlying proof of principle is already there.”
The reduction in SOD1 levels among the highest-dose tofersen group in the first study indicates “target engagement,” Dr. Hardiman said.
In that study, the documented decreased protein in the CSF appeared to be dose related, as was the effect for neurofilaments, which is biomarker evidence of neuronal damage, she noted.
In the second study, the pathologic evidence from the first patient also suggests “evidence of target engagement,” Dr. Hardiman said.
However, she added, “We don’t know very much about the outcome of the second case other than immunosuppression seemed to be beneficial.”
New hope
Both studies have caveats, said Dr. Hardiman. For example, it is unclear whether the treatments would be beneficial for every variant in SOD1.
“These are very expensive therapies, and we will need to have some level of certainty in order to be able to determine whether this should be a treatment for a patient or not,” said Dr. Hardiman.
She also noted that the studies were not powered to provide evidence of efficacy and that they raise questions about the accuracy of the ALSFRS-R.
One issue is that the respiratory part of that scale is “very insensitive”; another is that the scale doesn’t capture nonmotor elements, such as cognition and behavior, she said.
Utilizing a combination of the ALSFRS-R slope and survival would “probably be more beneficial,” Dr. Hardiman said.
Understanding how to alter the genetic influence in a disorder is important to be able to identify successful treatments, Dr. Hardiman added. For example, the discovery of the BRCA gene led oncologists to develop a precision medicine approach to the treatment of breast cancer.
In regard to ALS, by starting with subgroups that have specific genomic features, “investigators are providing new hope for patients at genetic risk for this devastating fatal disease,” said Dr. Hardiman.
The first study was funded by Biogen. The second study was funded by a fellowship grant from the Alzheimer’s Association, a Jack Satter Foundation Award, the ALS Association, the Angel Fund for ALS Research, ALS Finding a Cure, ALS-One, Project ALS, the Massachusetts General Hospital, the Max Rosenfeld and Cellucci Funds for ALS Research, and several senior members of Bain Capital. Dr. Ferguson is employed by and holds stock in Biogen. Dr. Brown receives grant support from the National Institute of Neurological Disorders and Stroke. He is also co-founder of Apic Bio. Dr. Hardiman is the editor-in-chief of the Journal of Amyotrophic Lateral Sclerosis and Frontotemporal Degenerations, has consulted for Cytokinetics, Mitsubishi, and Wave, and holds research grants from Novartis and Merck. During the past 2 years, she has also been a principal investigator on ALS clinical trials sponsored by Orion and Cytokinetics and is currently on the data and safety monitoring board of Accelsior.
This article first appeared on Medscape.com.