Below is a report on five leading ALS research strategies and a look at ongoing projects in each strategy:
ALS is a disease that holds tight to its many secrets, even after decades of relentless pressure by dedicated and well-qualified researchers.
Part of the complexity of ALS is that it involves multiple biological components and pathways, presents in many forms, and likely is caused, in whole or in part, by any of a number of genetic flaws or susceptibilities.
It follows then that there’s not likely to be a one-drug cure for ALS. Rather, patients probably will require drug or therapy “cocktails” that are uniquely tailored to their own set of genetic circumstances.
To speed the search for treatments that cover all forms of ALS, MDA’s research program essentially “paints broad brush strokes,” supporting research into a number of technologically and physiologically diverse experimental treatments.
Below is a report on five leading ALS research strategies — antisense oligonucleotides, stem cells, protein therapies, small molecules and gene therapies — and a look at ongoing projects in each strategy. (For a list of the types of targets these strategies might be aimed at, see Possible Targets for ALS Research.)
Antisense oligonucleotides — sometimes called antisense, oligos, or simply AONs — are synthesized, short, single strands of the chemical bases that make up DNA or RNA (the chemical step between DNA and protein production). Designed to pair up with a particular targeted sequence of DNA or RNA, AONs can change, block or destroy genetic instructions.
Early work by neuroscientist Don Cleveland, professor and chair of the department of cellular and molecular medicine at the University of California, San Diego School of Medicine in La Jolla, showed that AONs can reach nerve cells and neighboring support cells in the central nervous system. This important finding has paved the way for therapies such as one now under development for familial (inherited) ALS caused by mutated SOD1 genes that lead to the production of toxic SOD1 protein.
Note: Although the vast majority of ALS cases are “sporadic” (not inherited) rather than familial, both forms of the disease present with the same physical and biological features: motor neuron death, weakening and degeneration of the muscles, and central nervous system inflammation. Therapies that can target these and other symptoms of ALS likely will be effective in both forms of the disease. It follows that research into familial ALS has relevance for the sporadic form of the disease as well.
Since 2007, neurologist and MDA grantee Timothy Miller at Washington University in St. Louis has worked with Isis Pharmaceuticals of Carlsbad, Calif., on the development of the experimental antisense therapy ISIS-333611. Miller was a member of a study team that showed the drug, now called ISIS-SOD1-Rx, blocked production of SOD1 in the central nervous system and prolonged life in rats with a disease that mimics human ALS.
MDA-supported human testing of ISIS-SOD1-Rx began in March 2010 at five U.S. study sites. An external pump administers 12-hourlong infusions of the experimental treatment directly into the fluid that surrounds the brain and spinal cord. The delivery method, called intrathecal injection, is designed to get the AON compound past the blood-brain barrier and blood-spinal cord barrier, where it can inhibit the production of toxic SOD1 protein molecules.
Although the phase 1 trial still is under way, a phase 2 trial of ISIS-SOD1-Rx already is in the planning stages. Research fellow and current MDA grantee James Berry at Massachusetts General Hospital in Boston is a member of the study team now planning the trial, which will test the drug over an extended period of time to assess its safety and tolerability. If the phase 2 trial is successful, a phase 3 trial may be conducted to test the efficacy of the drug.
Although most current work on AON-based strategies in ALS is targeted to the SOD1 gene, such therapies likely would also apply to TDP43, FUS and other genes associated with ALS.
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Stem cells can be thought of as cells in the very early stages of development. They may be precursors to a specific cell type (such as muscle or nerve cells) or they may still retain pluripotency — the ability to develop into any of a number of different cell types.
The harvesting of stem cells from embryos has generated considerable debate, but scientists now have an alternative: induced pluripotent stem cells. These iPSCs are mature cells regressed or reprogrammed back into a “stemlike” state; from there they can be coaxed along the appropriate developmental path in order to become whichever type of cell is needed.
In ALS, disease-affected stem cells can be cultured for use as research models in which to study the disease process or screen potential therapeutic strategies. They also are in development as cell-transplantation therapies.
Clive Svendsen, director of the Cedars-Sinai Regenerative Medicine Institute in Los Angeles, gave a presentation about stem cell therapy in ALS at the 2011 MDA National Scientific Conference, March 13-16, in Las Vegas. He noted that this type of “regenerative medicine” might be used in a variety of ways. Theoretically, stem cells could:
- replace ALS-affected nerve cells (motor neurons);
- repair damaged motor neurons;
- encourage the body’s own mechanisms of cell and tissue repair to fix or replace damaged neurons;
- release supportive proteins called growth factors to provide support to dying motor neurons; or
- be used in combination approaches with other therapeutic agents.
Assistant professor and MDA grantee Alysson Muotri at the University of California, San Diego in La Jolla is working to generate a human cellular model of ALS using cells taken from individuals with a particular form of the disease called ALS8. The new model will be made available to the ALS research community and is expected to help scientists pinpoint biomarkers that can help with diagnosing ALS and predicting its course.
Francois Berthod, a professor in the department of surgery at Laval University in Quebec City, Quebec, Canada, also is working on the development of a new ALS research model.
Berthod, who has a background in tissue engineering, is using neural cells obtained from the tissues of people with ALS to create a three-dimensional model of the human spinal cord. The model’s design is expected to permit testing of the interactions of various neural cell types.
Clinical trial results reported in 2008 showed that transplanted mesenchymal stem cells, which are derived from bone marrow, entered the central nervous system from the bloodstream in six trial participants with ALS. MDA grantee Stanley Appel at Methodist Neurological Institute in Houston coordinated the study team. (Appel, director of the MDA/ALS Center at Methodist Neurological Institute, is a member of the MDA Board of Directors and chairman of MDA’s Medical Advisory Committee.) Although the approach was shown to be feasible and safe, there was no evidence of clinical benefit.
In January 2010, a phase 1 clinical trial was launched by the biotechnology company Neuralstem, of Rockville, Md., with the aim of determining the effects in ALS of neural precursor cells derived from a fetal spinal cord. The first U.S.-based trial of neural stem cells in ALS, it’s being conducted at the MDA/ALS Center at Emory University in Atlanta with Jonathan Glass, neurologist and director of the MDA/ALS clinic at that institution, serving as the onsite principal investigator. Twelve to 18 people with ALS will receive a single injection of fetal stem cells directly into their spinal cords.
Trial investigators hope to confirm the hypothesis that the stem cells will provide support to damaged neurons. At this early stage, however, the trial will focus only on safety, not efficacy. (See ALS Research Roundup November-December 2009: First US Trial of Neural Stem Cells in ALS Gets FDA Green Light.)
Studies on another stem cell approach to treating ALS have been conducted by neuroscientist Svitlana Garbuzova-Davis at the Center of Excellence for Aging and Brain Repair at the University of Florida in Tampa. Garbuzova-Davis’ work, supported in part by MDA, has suggested that stem cells might be used to repair blood vessels in the blood-brain barrier and blood-spinal cord barrier, both of which appear to be disrupted and abnormally permeable or “leaky” in ALS. Repair of these barriers, Garbuzova-Davis said, may help protect nerve cells.
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Proteins potentially may serve as treatments for ALS by compensating for nonfunctional, dysfunctional or missing proteins, or by interfering with proteins that are toxic to neural cells or to cellular subcomponents such as mitochondria.
In the 1990s, investigations began into the role of neurotrophic factors — proteins that support motor-neuron health and which have been reported to confer benefits in rodent models of ALS. However, industry-sponsored trials of ciliary neurotrophic factor (CNTF), glial-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) showed that none was effective.
The naturally occurring protein and antioxidant IGF1 also was tested in two 1990s clinical trials, with conflicting results. A “tiebreaker” trial, the results of which were reported in early 2009, showed the protein conferred no clinical benefit in ALS. Although it would seem IGF1 has scant potential as an ALS therapy, it’s been suggested that refining the protein’s structure or changing the method of delivery may change the outcome. (See ALS Research Roundup, January 2009: IGF1: Failure or Success as an ALS Therapy?)
Other efforts include those by longtime MDA grantee Michio Hirano at Columbia University in New York, and colleagues, who have tried various coenzyme Q10 (coQ10) variants.
In related work, Carlos Moraes, another longtime MDA grantee and professor at the University of Miami, Miller School of Medicine, has demonstrated in mice that increasing levels of the metabolism regulator PGC1-alpha increases cellular production of mitochondria.
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Synthesized small-molecule drugs are considerably smaller than proteins and many times smaller than cells. They are generally easier to deliver to targeted tissues than proteins or cells and are less likely to elicit an unwanted immune response.
One small-molecule approach in ALS involves using the molecules to activate neuroprotective pathways. This includes using small molecules to cause proliferation of neuroprotective glial cells.
Researchers conducting a phase 3 clinical trial of the small molecule ceftriaxone currently are recruiting ALS participants at 57 locations across the United States and Canada. Increased levels of the chemical glutamate have been linked to cell death in ALS; it’s hypothesized that ceftriaxone may increase the levels of a protein that decreases glutamate levels near motor neurons, protecting them from injury.
Ceftriaxone is an antibiotic that’s already been approved by the U.S. Food and Drug Administration (FDA) for the treatment of bacterial infections, but not for use in ALS. The phase 3 trial, which began in spring 2009, is led by neurologist Merit Cudkowicz (director of the MDA/ALS Center at Massachusetts General Hospital in Boston), and is designed to determine whether the drug slows loss of function and increases survival time in ALS.
Another small molecule, necrostatin 1, appears to inhibit the BNIP3 cell-death pathway. The potential for modulating the BNIP3 pathway to affect ALS is being studied by MDA grantee Jiming Kong, associate professor in the department of human anatomy and cell science at the University of Manitoba, Winnipeg, Canada.
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Gene therapy, or gene transfer, refers to the delivery of genes as therapeutic agents. Since genes carry the instructions for protein synthesis, they can lead to production of proteins that are directly or indirectly therapeutic in neuromuscular diseases. The opportunity exists with such therapies to target specific populations of cells with a long-lasting (possibly one-time) treatment.
MDA grantee Daniel Offen, head of the neurology laboratory at Tel-Aviv University, Israel, is working on a combination cell and gene therapy approach to treat ALS. Offen’s research involves engineering progenitor cells to express various combinations of neurotrophic factors. Mixtures of the engineered cells will be injected into muscles in the SOD1 mouse; Offen and his team will then monitor the mice for behavioral, physical and biochemical survival indicators in an effort to determine which combination of factors is most beneficial in terms of disease progression and survival time.
Gene therapy faces many technical challenges, as well as a high bar set by regulatory agencies such as the FDA. However, it’s expected that transferred genes would continue producing protein for some time, providing a more permanent fix than other therapies.
The key challenges for the strategy are delivering the genes to the targeted tissue while avoiding off-target tissues; and preventing or circumventing any unwanted immune system response to either the proteins made from the new genes or to the delivery vehicles in which the new genes are delivered. Getting around the immune system can be difficult, and the most effective delivery vehicles to date are derived from viruses — which the immune system is predisposed to attack.
Streamlining the search
Researchers in MDA’s ALS Clinical Research Network have made it a priority to create the infrastructure necessary for communication, collaboration, multicenter trials and connections with other ALS research networks.
With everything ready to go, all that’s needed is a breakthrough in these or other strategies. Then, like artists painting in the final strokes on canvas, decades of research can finally take shape in the form of therapies and cures to stop ALS.
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