At the largest-ever Drug Company Working Group meeting held in Boston in April, The ALS Association featured the first details of exciting new “antisense” target that may be relevant to most people with ALS, not just those with an inherited ALS gene. The meeting also featured reports from several companies that are forging ahead with novel approaches to ALS treatment. In addition, the meeting was the forum for the formal awarding of the Prize4Life $1 million Avi Kremer ALS Treatment Prize. Much of the work presented are direct results stemming from funding and academic-industry partnerships initiated by The ALS Association.

“With these many new treatments in development, this is an exciting time in ALS research” - Barb Newhouse, President and CEO of The ALS Association.

Some highlights:

Ataxin 2 is a Promising New Target for Most ALS

Dr. Aaron Gitler, Associate Professor of Genetics at Stanford University, explained why he thinks the ataxin 2 gene may be an important therapeutic target for most people with ALS. Several years ago, Dr. Gitler showed that variations in the length of the gene (and therefore in the length of the protein it made) affected the survival of fruit flies that carried a mutant form of TDP-43. TDP-43 proteins aggregate in almost all people with ALS (except for those whose ALS is due to mutations in either SOD1 or FUS), and researchers think this aggregation may be part of what drives the disease. That led Dr. Gitler to ask what contributed to the likelihood of TDP-43 aggregation, and that led him to ataxin 2.

In people, the usual form of the ataxin 2 gene carries a very short region of what are known as “CAG repeats,” which leads to a correspondingly short region of the protein made from the gene. Dr. Gitler found that when more CAG repeats were present, and thus a longer protein was made, it caused TDP-43 to aggregate more quickly, and led to neurodegeneration in the fly model of ALS he was using.

He wondered whether longer ataxin 2 genes could also affect ALS risk in people, not just in flies, and indeed he found longer-than-normal repeats in about 5% of people with ALS, whereas almost no repeat expansions were found in people without ALS. “These expansions are a powerful risk factor for ALS,” Dr. Gitler said, probably through their ability to increase aggregation of TDP-43.

The study showed that reducing the amount of expanded ataxin 2 was beneficial in animal models of ALS, improving survival and slowing neurodegeneration. This discovery alone would be highly significant at least for those people with ALS who carry the expanded ataxin 2 gene, because it suggests that reducing expanded ataxin 2 could be therapeutic. (Becker, et al., Nature, 2017)

But Dr. Gitler’s most recent work is potentially even more important than that, because it has now shown that reducing the amount of normal, non-expanded, ataxin 2 can also be beneficial in animal models. This suggests that almost everyone with ALS (most of whom carry a normal, non-expanded ataxin 2 gene) may benefit from a reduction in ataxin 2. In his work, Dr. Gitler showed this can be accomplished, at least in mice, with “antisense” technology, the same kind of treatment that was recently demonstrated to be safe in people with the SOD1 form of ALS.

“Ataxin 2 is a highly promising new target for ALS,” commented Dr. Lucie Bruijn, Chief Scientist for The ALS Association, “and the work on SOD1 antisense treatment, which The Association catalyzed through its funding, has laid the groundwork for rapid movement of this concept toward the clinic.”

New Approaches to ALS Treatment

In developing therapy for ALS, it is important to explore many different approaches. That’s why The ALS Association, through its TREAT ALSTM research portfolio, supports such a wide variety of researchers, biotech companies, and pharmaceutical firms in their search for new treatments. Five such organizations shared their programs for new ALS treatments during the meeting, including Teva Pharmaceuticals, Wave Life Sciences, Orphazyme, Karyopharm Therapeutics and Genentech.

Teva Pharmaceutical Industries, from Israel, is developing a drug called pridopine for Huntington’s disease to improve the health of neurons. Recent discoveries have revealed that one cause of ALS is a mutation that causes loss of activity of a cell molecule called the sigma-1 receptor. Pridopine acts to increase activity of the receptor, and thereby increase the level of a neuroprotective molecule called BDNF, which may be therapeutic in multiple forms of ALS, not just those caused by mutation in the receptor.

WAVE Life Sciences, in Cambridge Massachusetts, is focused on producing “stereopure” treatments aimed at specific genes. Antisense oligonucleotides (ASOs) are being developed to treat multiple forms of ALS. When ASOs are made in the lab, they are a mixture of so-called “stereo-isomers,” which are chemically alike but three dimensionally different, in the same way the left and right hands are made of similar parts but differ in 3D shape. This mix may be less potent than a purer compound. Wave’s technology reduces the unwanted stereo-isomers in the mix, potentially improving the potency of ASOs.

Orphazyme, from Denmark, focuses on promoting a natural cellular protective system called the heat shock response. They have acquired a drug called arimoclomol, which promotes the heat shock response. Arimoclomol proved promising in preclinical work in ALS, and there have been suggestions of benefit in small clinical trials as well. They are planning a phase II/III clinical trial in ALS to begin in the next year. The trial is to be led by Michael Benatar, of the University of Miami, and is supported by The ALS Association and the U.S. Food and Drug Administration.

Karyopharm Therapeutics, in Newton Massachusetts, creates therapies aimed at overcoming defects in “nuclear transport.” The cell nucleus regulates passage of many materials in and out of it. In ALS due to the C9orf72 mutation, as well as some other forms, nuclear import is impaired, which may contribute to disease by blocking return of molecules to the nucleus, including TDP-43. Animal models have shown that blocking the export of TDP-43 from the nucleus can be therapeutic. Karyopharm is developing nuclear export blockers to exploit this discovery. The ALS Association is funding several pre-clinical studies to accelerate this research.

Genentech, in San Francisco, California, is developing a drug called GDC-0134, which is now being tested in a phase I safety trial. The drug inhibits an enzyme that is overactive in ALS, called dual leucine kinase (DLK). DLK is thought to contribute to neurodegeneration when neurons become overexcited, as is thought to be the case in ALS. Thus, blocking DLK may be a useful treatment strategy.

Prize4Life: Avi Kremer ALS Treatment Prize

The group also witnessed the awarding of the $1 million ALS Treatment prize, named for Prize4Life founder Avi Kremer. The prize was offered for any research team that developed a therapy to increase the lifespan of the SOD1 mouse by at least 25%. Almost 30 teams competed. The winning team developed a method that improved survival in adult mice by 58%, far beyond what any previous therapy in SOD1 mice has been able to accomplish, and demonstrated delayed disease onset. The team was led by Drs. Martine Barkats and Maria Grazia Biferi of the Institute of Myology in Paris.