2016 Milton Safenowitz Fellowship Program for ALS Research Recipients
The Association is proud to support the development of bright, young scientists through the Milton Safenowitz Postdoctoral Fellowship. The Safenowitz family, through The Greater New York Chapter of The ALS Association, founded the award in memory of Mr. Safenowitz, who died of ALS in 1998. These awards are to encourage and facilitate promising young scientists to enter the ALS field. Fellows work with a senior mentor and receive extensive exposure to the ALS research community through meetings and presentations. After completing this fellowship, approximately 90 percent of the awardees stay in ALS research. They go on to establish their own laboratories to continue studying ALS and mentor more ALS researchers along the way.
Amanda Gleixner, Ph.D., University of Pittsburgh, Pittsburgh, Pa.
*Funding is also made possible by the Greater Philadelphia Chapter of The ALS Association
Title: Linking impaired nucleocytoplasmic trafficking in C9ORF72 ALS to altered nuclear pore complex O-linked N-acetylglucosamine (O-GlcNAc)
Summary: Proper cellular function relies on the transport of molecules between the nuclear and cytoplasmic compartments. However, deficits in nucleocytoplasmic trafficking have been observed in C9orf72-associated ALS but why this occurs in the disease remains unknown. Nucleocytoplasmic trafficking occurs through the nuclear pore complex. These studies seek to identify the cause of nucleocytoplasmic trafficking deficits by examining the composition of the nuclear pore complex in C9orf72 ALS. The nuclear pore complex is comprised of approximately thirty different nucleoporins. Nucleoporins can be modified by the addition of O-linked N-acetylglucosamine (O-GlcNAc) molecules. O-GlcNAcylation contributes to the selectivity and stability of the nuclear pore complex and promotes nucleocytoplasmic trafficking. However, a decrease in O-GlcNAc has been observed in ALS rodent models. Therefore, the investigators hypothesize that deficits in O-GlcNAcylation occur in C9orf72 ALS that, in turn, impair nucleocytoplasmic trafficking. These studies will examine O-GlcNAcylation of the nuclear pore complex in human C9orf72 ALS tissue and seek to reverse nucleocytoplasmic trafficking deficits and elicit neuroprotection by modulating O-GlcNAcylation.
Read more about Dr. Gleixner’s exciting research project and get to know the person behind the science.
Vicente Valenzuela, Ph.D., University of Chile, Santiago, Chile
Title: Gene therapy to attenuate ER stress alterations in ALS
Summary: ALS is a fatal neurodegenerative disease leading to paralysis and premature death due to dysfunction of neurons responsible to control body movements, termed motor neurons. The endoplasmic reticulum (ER) is the protein factory of the cell that is dramatically affected in ALS motor neurons. When proteins produced in the ER do not pass the quality control check, they accumulate as highly toxic waste. A fire alarm system called the ‘Unfolded Protein Response (UPR)’ is activated to restore the normal function of the ER by activating a gene expression program that aims repairing the damage. Importantly, ER homeostasis alterations are one of the earliest defects observed in ALS models, which may drive initial disease stages that trigger loss of motor control and later death of motor neurons. The investigators have obtained encouraging supporting results demonstrating that a gene therapy based on triggering an artificial UPR generates outstanding protection to ALS mouse models. In this project they will develop a systematic approach and define the relative contribution of ER stress to ALS. They have established a powerful collaboration network with key laboratories to move forward a novel gene therapy strategy to alleviate one of the major drivers of the ALS pathogenesis.
Read more about Dr. Valenzuela’s exciting research project and get to know the person behind the science.
Bruno Miguel da Cruz Godinho, Ph.D., University of Massachusetts Medical School, Worcester, Mass.
*Funding is also made possible by Chris Pendergrast.
Title: Silencing mutant SOD1 and C9orf72 in vivo using innovative hydrophobic siRNA scaffolds: a novel therapeutic path for the treatment of ALS
Summary: Therapeutic gene silencing holds great promise as a transformative clinical strategy for incurable, genetically-defined diseases, such as familial (inherited) ALS. The ability to suppress virtually any disease-related gene with high potency makes RNA interference (RNAi) an outstanding therapeutic platform for this purpose. However, despite recent clinical success in liver indications, delivery of synthetic RNAi-based drugs to the central nervous system remains a primary challenge in its application to neurodegenerative diseases. Thus, the goal of this proposal is to identify and develop a simple, efficient, and non-toxic delivery strategy for these RNAi drugs to enable silencing of ALS-defined targets SOD1 and C9orf72. The Khvorova laboratory has recently synthesized and validated the utility of a novel neuroactive hydrophobic siRNA (Di-hsiRNA) that exhibits high metabolic stability, efficient uptake in neurons, and potent gene silencing in the mouse brain. Using this innovative technology, in collaboration with Dr. Robert Brown Jr., they will validate the efficacy of these compounds against SOD1 and C9orf72 in the brain and spinal cord, and determine their functional therapeutic efficacy in established mouse models of ALS. The completion of this proposal will establish a foundation for the development of effective drugs for ALS and other neurodegenerative diseases.
Read more about Dr. Godinho’s exciting research project and get to know the person behind the science.
Sergey Stavisky, Ph.D., Stanford University, Stanford, Calif.
*Funding is also made possible by the Greater Philadelphia Chapter of The ALS Association
Title: Clinically-useful brain-machine interface control of a robotic prosthetic arm by people with ALS
Summary: The goal of Dr. Stavisky’s postdoctoral research in Stanford’s Neural Prosthetics Translational Laboratory is to provide people with paralysis due to ALS with an advanced brain-controlled robotic arm and hand that they can use to perform activities of daily living. Volunteer participants in the BrainGate2 clinical trial have had electrode arrays neurosurgically implanted in the motor areas of their brain. This creates a ‘brain-machine interface’ by which brain activity corresponding to the user’s movement intention is detected and ‘decoded’ into a command sent to the robotic arm. The arm and hand use state-of-the-art “smart robotic” control to assist the user in moving more dexterously. For instance, computer vision helps guide the hand more smoothly to the user’s goal object, and then force sensors in the hand automatically grip the object correctly. This multidisciplinary project combines expertise in neurology and rehabilitation to identify and prioritize types of movements to best help our patient population; neuroscience to accurately makes sense of the recorded brain signals; and robotics to assist the user and increase the range and precision of actions they can perform.
Read more about Dr. Stavisky’s exciting research project and get to know the person behind the science.
Tiffany Todd, Ph.D., Mayo Clinic Jacksonville, Jacksonville, Fla.
Title: Modeling selective vulnerability and disease specific functions in mice by the comparison of C9orf72 repeat models to a novel disease control
Summary: A repeat expansion in the gene C9orf72 is a common cause of ALS, but the mechanism by which it results in neuronal dysfunction and death is unclear. The repeat is transcribed into RNA that accumulates into foci throughout the central nervous system, and also undergoes a process known as RAN translation to produce toxic repetitive proteins. Repeat-positive ALS is also characterized by the accumulation of the protein TDP-43. Interestingly, a similar repeat causes the disease spinocerebellar ataxia type 36 (SCA36). This repeat also forms foci and similar repetitive proteins, but does not cause TDP-43 aggregation and affects different neurons. In this study, they aim to compare the effects of expressing the two repeats, C9orf72 and SCA36, in mice to determine what cellular functions are affected by the expression of the C9orf72 repeat and not the SCA36 repeat. They believe these functions will be most important for TDP-43 aggregation and ALS-specific deficits. They will also explore the role of the C9orf72 repeat in the cerebellum, a brain region that degenerates in SCA36, but not in ALS. Ultimately, if the investigators can understand why certain neurons respond differently to each repeat, they can use that knowledge to better understand and hopefully treat ALS.
Read more about Dr. Todd’s exciting research project and get to know the person behind the science.
Jeanne McKeon, Ph.D., University of Massachusetts Medical School, Worcester, Mass.
Title: Disruption of actin dynamics as a pathogenic mechanism in ALS
Summary: ALS is characterized by the degeneration of motor neurons, which are the neurons that control muscles. There is no cure for ALS and patients typically die within three to five years of disease onset. Although it is still unclear what causes ALS, much insight into disease mechanisms has been gained from genetic studies of patients with inherited or familial ALS. Among the genetic abnormalities identified are mutations in profilin 1 (PFN1), a protein that plays an important role in regulating actin dynamics. Actin is a critical cellular building block, which exists either in a monomeric or filamentous form. PFN1 helps convert actin monomers into filaments, which is important for many cellular processes including protein trafficking and for communication of neurons with muscles across synapses. PFN1 is important for organizing these sites of communication or synapses between neurons and muscles. This proposal will examine how PFN1 mutations contribute to alterations of cellular actin dynamics and actin-dependent cellular processes and whether these alterations cause neuronal cell death. This project will increase their understanding of the ALS disease process with the ultimate goal that these studies will aid in the development of novel therapies for people living with ALS.
Read more about Dr. McKeon’s exciting research project and get to know the person behind the science.
