To start, the Live Like Lou Center for ALS Research has recruited an expert in the neurobiology of ALS. The Center also has plans to:
- Develop a non-human primate model of the disease.
- Support clinical trials to slow or reverse the progression of ALS.
- Award “discovery” grants to catalyze novel research approaches.
- Promote quality-of-life research through neurotechnology.
Examine the neurobiology of ALS. Basic science is key to finding effective treatments and, eventually, a cure for ALS. Following a nationwide search, we have hired a first-rate young scientist, Christopher Donnelly, PhD, who has joined the faculty to conduct fundamental research to reveal the etiology and pathophysiological mechanisms of action of this devastating disorder. Dr. Donnelly was a postdoctoral fellow with world-renowned ALS expert Jeffrey Rothstein, MD, PhD, at Johns Hopkins University, where he used a variety of approaches to reveal the molecular mechanisms that underlie neural injury in ALS and frontotemporal dementia (FTD). Specifically, Dr. Donnelly generated neurons from the skin cells of patients who carry a C90RF72 hexanucleotide repeat expansion, the most common genetic cause of familial and sporadic ALS and FTD. Generation of these neurons enabled studies of the toxic mechanism behind this mutation and, in collaboration with industry, targeted the toxic product of this mutation to restore neural health. Dr. Donnelly’s studies helped in moving these therapeutics into the clinical trial pipeline. More recently, Dr. Donnelly and his collaborators identified a pathogenic mechanism that seemingly affects the majority of ALS patients and might explain a universal pathology observed in the disease. A PhD in molecular biology and genetics from the University of Delaware/Alfred I. Dupont Hospital for Children, Dr. Donnelly was mentored by Jeffery Twiss, MD, PhD, and studied the role of mRNA transport and localized translation in determining axonal growth programs and axon regeneration following injury. Dr. Donnelly has published a number of high-profile papers in Nature, Nature Neuroscience, and Neuron.
Develop a non-human primate model of the disease. One critical path to progress in treating, preventing and curing ALS lies in developing a model that mirrors the condition in people. An estimated 94 percent of NIH-funded research on the nervous system is performed on rodents. While a great deal of promising research has been conducted in mice and rats, and even in flies, so far at least 20 clinical trials based on experiments in rodents have been unsuccessful in developing an effective treatment for patients with ALS. Perhaps this should not be surprising, because there are crucial differences in the organization of the motor systems between rodents and primates. At the same time, there are important similarities between certain species of monkeys and humans in the organization of the neural systems that control movement. If our goal is to define the neural basis of this neurodegenerative disorder, then non-human primate models are essential.
Support clinical trials to slow or reverse the progression of ALS. One of the first trials the Center will support is a diaphragm-pacing study. Among the most frightening aspects of ALS is that it makes breathing difficult. This study is designed to test whether the NeuRx® Diaphragm Pacing System™ (DPS) improves diaphragm function so that patients can breathe better. David Lacomis, MD, is Director of Clinical Research in the Live Like Lou Center, and also directs Pitt's multi-disciplinary clinic, the MDA-ALS Center.
Award “discovery” grants to catalyze novel research approaches to ALS. This pilot-project program is designed so that any faculty member with a good idea can jump in and do novel experiments that traditional granting bodies might pass on, without preliminary data to prove that they might work. We believe in the discovery process. It’s only by giving people the opportunity to tackle challenging questions that we are going to make major discoveries.
Promote quality of life through neurotechnology. We intend to build on our expertise in brain-controlled robotic arms and hands for quadriplegic individuals to provide brain-computer interface (BCI) technology that will allow people with ALS to maintain more control over their daily lives. As part of this effort, we will create a prototype Smart Home near our NeuroTech Center, now under development on Pittsburgh’s South Side. The Smart Home living space, in an accessible apartment two blocks from our neuroengineering labs, will enable mobility-impaired patients to spend days and nights at a time, trying out and choosing items that they would like to have installed in their own homes. These will include powered mobility assistants, devices that sense and monitor the environment and the patient’s needs, and improved, higher-speed communication devices for patients who have lost the ability to speak.
In some cases, our patient-subjects will be directly involved in the development of new BCI technologies. This includes the use of telemetry (much like Bluetooth technology) so that these devices can be used at home and out in the community, rather than only in test labs. Our test subjects with extensive paralysis have shown that they can use their own neural signals to operate a highly anthropomorphic prosthetic arm. We intend to expand this tapping of neural signals so that patients can use brain-controlled robotic arms mounted to wheelchairs to perform daily tasks. Additional research will also allow patients to operate computers with their thoughts, so that they are not completely “locked in” and are able to communicate more easily than with current speech-generating devices and eye-gaze systems.
Some devices for the Smart Home do not involve brain control, and either are already available, or will be soon, through the Human Engineering Research Laboratories and the Center for Assistive Technology at Pitt, and through the Robotics Institute at Carnegie Mellon University. This technology includes transfer devices that reduce physical strain on family members. The Strong Arm, for instance, is a portable device that allows a caregiver to lift a wheelchair-bound person to another surface with just one finger, by directing a handle on the end of the arm. Other devices include smartphone remote control applications (e.g., for light switches, heating and air conditioning, TVs and computers, opening doors, etc.) and kitchen devices that include an overhead, track-mounted manipulator that helps with tasks such as turning on water faucets and handling kitchen ware.
Use of ALS patients’ stem cells for basic discovery. New technology allows researchers to study ALS in cells developed from patients with the disease. Investigators take skin samples and isolate specific cells called fibroblasts to derive induced pluripotent stem (iPS) cells. These iPS cells are then directed to differentiate into motor neurons and supportive glial cells that have the characteristics seen in ALS. The neurobiology of the cells should tell us about disease mechanisms and why disease characteristics vary so much from one individual to another. They will also provide a foundation for testing drugs to determine which ones should move forward and be tested in patients. Scientists in Pitt’s Neuroapoptosis Lab anticipate that a multi-drug regimen, comparable to the “cocktail approach” used to treat AIDS and some cancers, may be found that will prevent the death of motor neurons.
Discovery and validation of biomarkers. We are examining serial samples of blood and spinal fluid that has been collected every four months from volunteer ALS patients, as part of a multi-center study with Massachusetts General, the Barrow Neurological Institute in Phoenix, Emory University, and the Mayo Clinic in Jacksonville. This research is expected to reveal information about the underlying cause of ALS, as well as to identify unique biological markers, which could be used to develop new therapies.