Basic

Genetic Modifiers of Disease in the SOD-1 and Dynactin Mouse Models

We have observed that survival in the transgenetic mouse model of ALS (G93A SOD1) is dependent on the mouse background. The original mouse model was created on a mixed background of two different strains called SJL and B6. When mice are mated to create either a pure B6 or SJL background, we observed that mice with a B6 background survive longer than those with the SJL background. We hypothesized that this was due to specific differences in genetic information between the two backgrounds, and that these genetic differences modified the severity of disease. In fact, we have now identified an area on mouse chromosome 17 that modifies disease, and our lab is actively working to identify the specific gene on this chromosome that is responsible in collaboration with Greg Cox at Jackson Laboratories. This project could provide a therapeutic target in human disease to help improve the outlook for people living with ALS. We are also studying whether this effect is observed for other models of motor neuron damage. In fact, we have now found similar differences in the severity of disease in the dynactin mouse, another genetically-engineered model based on the mutated dynactin gene, and we chromosome 17 modifiers may also be responsible in this case. This is exciting because it means that similar modifiers could affect many different types and models of motor nerve damage, so a possible treatment based on this information could be more universally applied. We will now be examining our potential modifying genes in other disease models including worm models. This work was recently published in the journal PlosOne.

Developing a Better Model of Human Disease: The VLE SOD1 Model

The mouse model of ALS most commonly used for experiments has 24 copies of the abnormal SOD1 gene; this mouse dies very young. Once the disease starts, there is a rapid progression. Since ALS in people occurs later in life and is slower in progression, we have developed a model of disease that starts later and progresses more slowly by decreasing the number of mutant SOD1 gene copies to only four. We call this our VLE (very low expression) SOD1 model and feel that it more accurately reflects the disease in humans. This work was recently published in the journal PlosOne. We have characterized this animal and are now using it to study early events and environmental conditions that may precipitate disease.

Developing Other Models of Motor Neuron Disease: Spastin Models

Hereditary Spastic Paraplegia (HSP) is a neurodegenerative disorder affecting only the upper motor neuron, resulting in motor system involvement similar to ALS and PLS. Mutations of the spastin gene are the most common cause, accounting for over 40% of HSP cases. We have now created a new genetic mouse with inducible expression of a human spastin mutantation andare characterizing the mouse to see if it exhibits motor weakness and disease. If the animal develops spasticity, it will provide a model of PLS and HSP to study mechanisms of upper motor neuron damage. This mouse will also be useful for design of treatment strategies for PLS and HSP as well as ALS.

Developing New Therapeutics

We are working with LifeSplice, a biotech company, to develop agents that can alter the form of proteins that are damaging to nerve cells. We call these agents splice modulating oligomers because they alter the way DNA is cut up or spliced to make RNA, the process that determines which variation of a protein is made by your cells. In people with ALS and other motor neuron diseases, these toxic proteins lead to nerve cell death. By altering these proteins, we might be able to slow or stop the disease process. Our splice modulating molecules are now being tested in animals for safety.

In addition, we are working in collaboration with the Pharmacology Department at Drexel University College of Medicine to test potential drugs that alter sigma 1 action on nerve cells in our mouse models of ALS. Sigma 1 signalling is important for nerve cell survival and function. A mutation in the gene for sigma 1 is responsible for some cases of familial ALS.

The MDA/ALS Center of Hope at Temple University Lewis Katz School of Medicine provides an important setting for research towards understanding, treating, and curing ALS. That is why the ALS Hope Foundation supports an extensive clinical research program at the Center of Hope. Without research, there would be no progress in our fight against ALS. Clinical Research is a broad term, encompassing clinical trials (studies on the effect of a medicine on the disease or its symptoms) and clinical research that examines other aspects of the illness, such as assistive technology or quality of life. Clinical research at the Center complements our basic research program, in the hope that promising therapeutics identified at the lab bench can be tested for efficacy in the clinic.