ALS TDI Conference Summarizes ALS Research Progress

Themes discussed throughout the research symposium included ALS genetics, clinical trials, the role of the immune system in disease onset and progression, biomarkers, and the use of stem cells in ALS therapeutics.

A comprehensive overview of ALS research challenges and successes was presented at the 2010 Leadership Summit hosted by the ALS Therapy Development Institute (ALS TDI) on Oct. 4.

The Summit, an annual two-day event in Cambridge, Mass., featured lab tours on Oct. 3, followed by a research symposium on Oct. 4 which was broadcast live on the Internet.

CEO and Chief Scientific Officer Steve Perrin updated researchers, clinicians and families on the status of the Institute's drug development pipeline for ALS, and speculated about a possible "new era" in drug development as smaller biotech companies are consumed by larger corporations.

In addition, the MDA-supported nonprofit biotech hosted experts from outside the organization to discuss a variety of topics, including ALS genetics, immune system modulation, clinical trials, the need for identification and development of biological indicators called "biomarkers," and stem cell therapeutics.

The event webcast is archived on ALS TDI's website: See Leadership Summit. (Registration is required.)

ALS TDI — pipeline progress

Perrin reported that as ALS TDI searches for pharmaceutical partners to help move its lead therapeutic candidate, ALSTDI-00846, into clinical trials, work continues on other drugs of interest in the Institute's pipeline.

ALS TDI's pipeline funnels promising experimental treatments through the beginning stages of drug development.

ALSTDI-000876 (NTF5) — Evidence in cell culture and animal models of spinal cord injury suggest this drug is neuroprotective and promotes growth at the neuromuscular junction (the place where nerve cells connect to muscles). In testing at TDI, the compound failed to provide any benefit in SOD1 mice, and may have made them worse.

ALSTDI-000866 (apocynin) — Previous study results of apocynin revealed a dramatic decrease in neural toxicity in an ALS model, but in testing at TDI it failed to confer any benefits.

ALSTDI-000896 — Although this drug produced some intriguing results in Alzheimer's studies, it also showed no benefit in testing at ALS TDI.

ALSTDI-000486 — This small molecule appears to inhibit the infiltration of immune  system cells to sites of injury such as damaged neurons.

ALSTDI-00903 — Another drug aimed at modulating the immune system, 00903 appears to selectively deplete toxic T cells.

The productivity model: A 'new era' of drug discovery?

As the second day of the summit began, news circulated about the bid of global pharmaceutical company Sanofi-Aventis to take over the biotech company Genzyme, headquartered in Cambridge, Mass.

The acquisition is the latest in a trend that has seen a score of biotechnology companies bought out by big players in the pharmaceutical industry. These include the March 2009 buyout of Genentech, formerly headquartered in San Francisco, by Swiss pharmaceutical conglomerate Hoffman-Roche, and the 1996 acquisition of the biotechnology research and development company Genetics Institute Inc., of Cambridge, Mass., by pharmaceutical giant Wyeth — which was itself acquired by Pfizer Inc., in October 2009.

Perrin cited a profit motive for the trend, noting that the pharmaceutical companies' efforts are aimed at increasing productivity of the drug development model — one that has seen an overall decline since 1994 in the number of new drugs approved each year by the U.S. Food and Drug Administration (FDA) despite:

  • a dramatic increase in the amount of funding committed to research and development;
  • advances in technology such as the addition of automated robots to the high-throughput screening technique that allows chemists to screen hundreds of thousands of diverse compounds in search of one or more that produce a desired effect; and
  • the sequencing in 2003 of the entire reference human genome (the complete set of DNA, akin to a "genetic blueprint"), an accomplishment many thought would lead to a flood of cures for human diseases, but from which relatively few results have been realized.

Researchers are doing good work, Perrin said, "but we've found the easy hits." Now researchers are pursuing "complicated diseases with complicated biology," and it's simply going to take longer to get effective medications to the people who need them.

Perrin noted that 70 percent of experimental drugs make it through the preclinical and phase 1 stages of development, at an average cost of eight years and $8 million, only to fail in phase 2 testing.

Reducing these statistics, Perrin said, requires a higher standard of work through the early stages of drug discovery and development. This is where nonprofit organizations can take the lead as they work with pharmaceutical companies, the National Institutes of Health (NIH) and the academic research community to speed the movement of potential therapies from lab to clinic.

Fernando Vieira, ALS TDI director of in vivo validation, addressed three areas of ALS research that garnered a lot of attention in 2010: genetics, stem cells and immune system modulation.

Genetics: The TDP43 research mouse

Fernando Vieira discussed animal research models of ALS, including the SOD1 and TDP43 mouse models.

Mutations in the gene that carries instructions for the TAR-DNA binding protein (TDP43) were identified in 2007 as the cause of 2 percent to 6 percent of familial ALS cases, and some sporadic (not inherited) cases. This spurred a number of research projects aimed at developing TDP43-based animal research models. The first — a rat model — became available in 2010. Scientists use such models as tools to understand and test therapeutics for human disease.

A number of models have been created using flies, worms, mice and rats, but one in particular — a mouse model engineered to overexpress human mutant TDP43 protein in the central nervous system — has caught the attention of ALS TDI.

The TDP43 mouse, developed with MDA support (see New ALS mouse), exhibits a number of the same symptoms that characterize human ALS, including weight loss and an abnormal gait. The TDP43 protein, which normally resides in the cell nucleus, forms clumps in the main part of the cell and the mouse experiences motor neuron (nerve cell) loss, muscle atrophy and shortened life span.

ALS TDI has geared up to add the TDP43 mouse model to its preclinical research program, with plans to study the model's disease process, survival time, disease-modifying gender effects and the safety and efficacy of potential therapeutics. (For more on ALS TDI's mouse studies see Building a Better Mouse: How Animal Models Help Fight ALS.)

Stem cells

Vieira commented on the growing popularity of induced pluripotent stem cells (iPS), which are created by taking mature cells from humans and regressing them to a "stemlike" state, where they then can be coaxed into becoming any type of cell in the human body. Such cells can be used both to study the ALS disease process and screen candidate therapeutics.

A motor neuron stem cell line already has been produced for use in drug screening. The line was developed with ALS-affected cells regressed to the pluripotent stage and then prompted to develop into neurons.

Also of current interest in the ALS stem cell arena is an ongoing phase 1 clinical trial sponsored by the biotechnology company Neuralstem of Rockville, Md.

The trial, which opened in September 2009, is being conducted at Emory University in Atlanta. Jonathan Glass, neurologist and director of the MDA/ALS clinic at that institution, is serving as the onsite principal investigator. (See First US Trial of Neural Stem Cells in ALS Gets FDA Green Light.)

The investigators plan to test the hypothesis that the stem cells will support damaged neurons. At this early stage, however, the trial will focus only on safety, not efficacy.

"It's a prominent topic," Vieira said, adding that it's important to temper any excitement or expectations for benefit with the reality of the study's goal.

Vieira also updated viewers on ALS TDI's collaboration with California Stem Cell in Irvine, Calif., ongoing since 2008.

The investigators have confirmed that although stem cells injected into the spinal cords of SOD1 mice form neurons, the new nerve cells do not extend axons (long fibers that carry nerve cell signals to the spinal cord or directly to muscles). Although the cells don't innervate (send nerve signals to) muscles, Vieira said, the hope is that they will provide support to diseased motor neurons in the mice.

To that end, the researchers now are executing an efficacy study, also in SOD1 mice, to determine whether the stem cells provide any benefit.

Immune system in ALS

The hypothesis that a number of factors contribute to the ALS disease process has gained near universal acceptance among researchers, and key players in the immune system keep "popping up" in investigations, Vieira said.

Although immune system involvement of neuron support cells called microglia has been implicated by some scientists for years, recent work at ALS TDI on its lead therapeutic candidate ALSTDI-00846 has demonstrated a role for other areas of the immune system as well.

Vieira noted that ALS TDI has an "extensive" immune-modulation project portfolio including small molecule, protein and gene therapy approaches.

For the first time since initiating its annual leadership summit, ALS TDI invited experts from outside ALS TDI to weigh in on major themes in current ALS research.

A panel discussion set the stage for experts to answer questions from both the audience and online viewers. From left to right: Fernando Vieira, Clive Svendsen, Merit Cudkowicz and John Lincecum.

Guest speakers included Merit Cudkowicz, an MDA research grantee and director of the MDA/ALS Center at Massachusetts General Hospital in Boston; Gilmore O'Neill, vice president of experimental neurology at Biogen Idec, headquartered in Weston, Mass.; and Clive Svendsen, director of the Cedars-Sinai Regenerative Medicine Institute in Los Angeles.

What’s taking so long?

Cudkowicz, who also is a member of MDA's Medical Advisory Committee, discussed clinical trials and the pace of discovery in ALS research.

Although ALS was first described in 1873, the bulk of scientific advances in the field have come since the 1993 breakthrough discovery of the first gene known to cause ALS. This, Cudkowicz explained, is the reason cures haven't been developed yet. Pinpointing the SOD1 gene provided the first clue to the disease process. The discovery brought in more scientists to the field and allowed for the creation of an ALS research model.

The discovery of more genes brings in more scientists, Cudkowicz said. "The community keeps growing, bringing in new people who are excited to understand and develop therapies for ALS."

The field today has a host of new theories on disease mechanism; has made progress in therapeutic development; and is feeding a large and continually growing drug development pipeline of potential therapies. Some of the major challenges include the length of time it takes to bring a drug from lab to market; the small number of pharmaceutical companies interested in pursuing treatments for ALS; and decreases in government and other funding for research.

Cudkowicz described in detail the ins and outs of clinical trials including trial design, phases, requirements, oversight, purposes, and ALS-specific challenges such as the need for large numbers of participants to realize valid results and the need for reliable biological indicators to judge disease progression and effects of treatment.

Experimental treatments currently undergoing trials in ALS include:

Despite the various difficulties associated with testing candidate therapeutics, "clinical trials are critical to finding the cure for ALS," Cudkowicz said, and every effort should be made to facilitate the process for potential trial participants.

Developing biomarkers

O'Neill reported on the need to identify and develop clinical biological indicators, called "biomarkers," as a means to deriving more reliable results in ALS clinical trials.

Proof-of-concept trials are designed to confirm successful delivery of the optimum dose of a therapeutic to its intended target in the body for a specified period of time. Unfortunately, most of these studies produce negative results.

"By far the worst outcome," O'Neill said, "is 'failed,' in which results are negative, but in addition the scientists are unsure of whether they hit the intended target or whether the target was correct in the first place." Such results represent wasted effort and may cause researchers and other groups to balk and raise questions about continuing the line of study. Biomarkers can help prevent failed outcomes.

There are many types of biomarkers. The most common types may be biochemical, such as the presence or absence of proteins in tissues, spinal fluid or blood; and images obtained through MRI and CT scans.

Three categories of clinical biomarkers could dramatically improve the ALS drug development process, mitigating risk and helping eliminate "failed" study results.

  • ALS-specific biomarkers can be used to indicate disease status and track progression. They could be useful in diagnosis, prediction of disease course, and defining the patient population best suited for a particular clinical trial.
  • Therapy-specific biomarkers (also called clinical or pharmacodynamic biomarkers) can be used to determine a drug's optimal dosage and also to determine whether an experimental treatment reaches its intended target.
  • Clinical outcome biomarkers are specific to both ALS and the effects of a particular class of experimental drugs. These markers indicate whether a treatment is having an effect.

The goal in developing therapeutics is to be able to confirm that the right drugs are being delivered to the central nervous system, that the intended targets are being engaged, and that the desired biological and biochemical responses are being obtained, O'Neill said. Ultimately, biomarkers can answer a crucial question for clinicians and researchers: Is what I think I'm seeing actually the reality of the situation?

Stem cell approaches in ALS

Svendsen presented data on an area of study that has "exploded" over the last few years: stem cell therapy in ALS. This type of "regenerative medicine" aims at using stem cells to replace motor neurons; repair damaged motor neurons; encourage the body's own mechanisms of cell and tissue repair to fix or replace the damaged neurons; or release supportive proteins called growth factors to support dying motor neurons in ALS. Their ability to do this is a result of their "pluripotency"— that is, the ability to mature into any type of cell.

Stem cells also bear a great potential for modeling ALS, providing scientists with an additional tool to study characteristics and mechanisms of the disease.

Although questions of ethics continue to hamper widespread use of embryonic stem cells, scientists now have an alternative: induced pluripotent stem cells (iPS). These are adult cells that are regressed to their earlier, pluripotent stage. From there, they can be coaxed into becoming whatever type of cell is desired.

Four approaches to treating ALS with stem cells include "snake oil;" blood and mesenchymal stem cells; neural stem cells; and combination approaches.

"Snake oil," Svendsen said, "is the unfortunate side effect of the excitement of stem cells." It involves individuals and companies touting "cure-alls" and establishing clinics around the world where they charge anywhere from $20,000 to $50,000 to “cure” ALS and all manner of other diseases. These so-called treatment facilities create confusion and distract from legitimate stem cell studies and trials, Svendsen said. Individuals and families interested in stem cell therapies can visit the International Society for Stem Cell Research website for reliable facts and updates in the study of stem cell therapeutics.

The rationale behind the use of blood and mesenchymal stem cells is not replacement of neurons, but support through the release of proteins called growth factors and modulation of the immune system. Several studies have shown that these treatment cells don't get into the brain, but seem to have a peripheral effect.

Neural cells derived from embryonic or induced pluripotent stem cells can be coaxed to develop either into neurons or neural support cells. Studies have shown that replacement of neural support cells called “astrocytes” is neuroprotective in a model of motor neuron disease.

Combination approaches involve first blocking, deleting or removing mutant SOD1 (or other disease-modifying proteins) from existing astroglia, then transplanting stem cells primed to become astrocytes or other support cells.

A number of blood and mesenchymal stem cell trials in ALS now are under way. Also, the Neuralstem trial in Atlanta (see 'Hot Topics' above) involves the injection of neural stem cells into the spinal cords of ALS patients (see First Human Stem Cell Trials for ALS to be Conducted at MDA/ALS Center in Atlanta).

Svendsen reported that no adverse events related to Neuralstem's stem-cell delivery procedure have been observed, and minimal pain experienced by trial participants following surgery resolves quickly. Investigators have seen, however, indications of possible immune system challenges.

Svendsen also noted that a second trial already is in the planning stages as a follow-up to the trial at Emory. Preclinical safety studies are expected to begin in the next few months. Patient enrollment is not yet open.


Next up

ALS TDI will present a recap of the 2010 Leadership Summit Oct. 19, at 7 p.m. Eastern time. To view the webcast, visit the Institute's website (www.als.net), click on "Get Involved," followed by "Research Update." (Registration is required.)

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