Progression of amyotrophic lateral sclerosis (ALS) can be slowed down by a new gene therapy

Researchers at Umeå University demonstrate that a novel gene treatment has significantly slowed down the disease development in a patient with an extremely severe type of ALS illness.

Research on the illness known as amyotrophic lateral sclerosis (ALS) has made significant progress. Researchers at Umeå University reveal that novel gene therapy has significantly slowed down the disease development in a patient with an extremely severe type of ALS illness. The patient is still able to go upstairs, get out of his chair, eat and speak normally, and lead an active, fulfilling life in the social world four years after starting the drug.

I consider this a breakthrough for the research we have conducted for more than 30 years, here at Umeå University and University Hospital of Northern Sweden. We have never before seen treatment results as effective as these, using any other treatment.

An important discovery is that it is now possible to considerably reduce the levels of the disease-causing SOD1 protein, and simultaneously measure a clear inhibitory effect on further disease progression. When we diagnosed the patient at the neurology ward in early spring 2020, the patient’s prognosis was 1,5–2 years of survival at best. The patient has far, far exceeded expectation.

Peter Andersen, a neurologist and professor at the Department of Clinical Sciences at Umeå University

The patient comes from a family in southern Sweden that suffers from a very severe case of ALS brought on by a mutation in the SOD1 gene. The patient did not want to know the findings of the genetic test, but after learning that a cousin had been diagnosed with ALS, she sent a blood sample to the Umeå University ALS research team for study. But the patient also carried the illness gene, and he discovered he was affected four years ago when he started to experience muscle weakness. The University Hospital of Northern Sweden’s medical staff saw the patient right away, and an early stage of ALS illness was identified.

The patient has been involved in a phase 3 trial sponsored by Biogen, a pharmaceutical business, since the summer of 2020. The study is aimed at assessing a novel gene therapy designed for patients with SOD1 mutations that result in misfolding and aggregation of SOD1 protein in motor neurons. At a university hospital in Copenhagen, Denmark, the patient has been receiving experimental therapy every four weeks.

The patient had extremely high levels of neurofilament L, a biomarker for the degeneration of nerve cells, at the time of diagnosis in 2020. After four years, the levels had dropped by over ninety per cent.

When the patient was diagnosed at University Hospital of Northern Sweden in April 2020, we measured the level of neurofilament L to be as high as 11,000 nanograms per litre, which is high even for an ALS patient. In the most recent sample, after 50 injections of the new drug, the level is down to 1,200 to 1,290, which is a substantial decrease of the disease indicator. The normal level for a person in the patient’s age group is below 560. In blood, the level of neurofilament has fallen back to normal levels, and was down to 12 during the latest hospital visit. The normal level is less than 13

Peter Andersen

According to the ALSFRSR scale, the patient’s level of function is lower than that of a healthy person (48 points), but it has remained relatively stable over the past 18 months, ranging from 35 to 37 points. This indicates that the patient’s functional level is lower than that of a healthy person by about 26%.

The patient usually loses 1-2,5 points each month if they have this extreme kind of ALS gene mutation. This indicates that in the absence of therapy, the disease would have progressed far more quickly than predicted, resulting in significant handicaps in 6–12 months and, most likely, the patient’s death in 2021.

To have succeeded with a drug treatment in this way is a great success and an inspiration. But it does not in any way mean that the job is done. This is just the beginning. It is also important to remember that the drug in question does not constitute a curative treatment, but it seems able to put the brake on disease progression. It gives us great hope to further develop pharmaceutical treatments for ALS-patients.

Karin Forsberg, a neurologist and researcher

Just 2 to 6 per cent of cases of ALS illness are due to mutations in the SOD1 gene. There are several forms of ALS disease. While many people have a family type of illness, so-called sporadic occurrences of ALS have also been linked to mutations in SOD1.

Whether this drug has a similar effect on other types of ALS disease is currently unknown. There is need for much more research on the subject.

Peter Andersen

The patient remains able to perform nearly all of the activities he was able to perform when he initially enrolled in the research in the summer of 2020. He can speak normally, takes care of his kids, shops, and mows the yard on his own. He also feels far better mentally, mostly because he dares to have optimism again.

However, until the Dental and Pharmaceutical Benefits Agency has submitted a health economic review, the New Therapies Council of Sweden has requested that the regional healthcare providers refrain from prescribing the medication.

Our next step is to study the results from the patients receiving this drug. It has worked for some, but not all have seen the same positive effect. It could be a question of dosage, or at which disease stage the treatment was initiated. Maybe additional drugs are required to completely stop the process? Those are questions we now have to try and answer. This is only the beginning.

Karin Forsberg

In her vision of the future, the type of ALS a patient has will determine the course of therapy, which will very certainly involve a mix of medications. She highlights that a great deal of research is being done in Sweden and throughout the world to identify novel targets for pharmaceuticals, with the aim that this may lead to the development of comparable medications for patient populations suffering from various forms of ALS.

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We can measure in samples collected from the patient that the disease process is ongoing, but the patient’s body seems able to compensate. Even now, four years after the patient started taking this new gene therapy drug. The Swedish Ethical Review Authority approved participation in these studies and now, several years later, we, as well as ALS physicians in other participating countries, see a clear clinical effect on many treated patients,

The next step will be to get approval from the Swedish Ethical Review Authority to study the compensatory mechanisms that treatment with this drug seems to have activated. There might be an opportunity here to get insights into how previously unknown parts of the nervous system work, and to develop even better new drugs.

Peter Andersen

Source: Umeå University News

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