Mohamed Farah, assistant professor of neurology and neuroscience at Johns Hopkins School of Medicine in Baltimore, was awarded an MDA research grant totaling $300,000 over three years to investigate whether a drug currently in development for Alzheimer’s disease can improve function in ALS (amyotrophic lateral sclerosis).

It’s thought that repair and regrowth of motor nerve endings might result in restoration of function for motor neuron diseases such as ALS — particularly slowly progressing forms.

In previous work, Farah and colleagues discovered that manipulating the amount of BACE1, an enzyme whose job it is to cut other proteins into pieces, enhances peripheral nerve regeneration in mice. Those studies prompted the team to explore the possibility that using a drug to reduce BACE1 might be an effective means to encourage motor axon regrowth at an early stage of motor neuron disease in mice.

Because BACE1 inhibitors currently are being developed and tested as potential therapies for Alzheimer’s disease, Farah’s work could lead to rapid development and clinical evaluation of BACE1 inhibitors in motor neuron diseases. If successful, the approach could enhance the quality of life of people with ALS or other motor neuron diseases.

Funding for this MDA research grant began Feb. 1, 2017.

Fen-Biao Gao, professor at the University of Massachusetts Medical School in Worcester, was awarded an MDA research grant totaling $300,000 over three years to identify new drug targets for ALS (amyotrophic lateral sclerosis).

C9ORF72 repeat expansion is the most common genetic mutation known to cause ALS. In this and several other forms of the disease, damage to DNA has been identified as a common, downstream pathway that can contribute to the death of nerve cells called motor neurons.

To understand how the C9 mutation drives the disease, Gao and colleagues have generated induced pluripotent stem cells (iPSCs) from C9 ALS patients and developed them into motor neurons and cortical neurons that recapitulate some key features observed in diseased cells, such as abnormal accumulation of RNA “clumps” and production of unusual toxic proteins. The team will use the iPSC-derived motor neurons as well as fruit fly models of ALS to investigate what causes DNA damage, and will perform a screen to identify new drug targets based on the findings.

Gao’s work will greatly enhance understanding of ALS disease mechanisms and may lead to the identification of key components in the DNA damage pathway that may serve as targets for therapy development.

Funding for this MDA research grant began Feb. 1, 2017.

Jie Jiang, postdoctoral fellow at the Ludwig Institute for Cancer Research, University of California – San Diego, in La Jolla, Calif., was awarded an MDA development grant totaling $180,000 over three years to improve understanding of the disease mechanisms underlying the most common inherited form of ALS (amyotrophic lateral sclerosis).

Expanded repeated sections of DNA (GGGGCC hexanucleotide repeats) in a non-coding region of the C9ORF72 gene have been identified as the most common genetic cause of ALS and frontotemporal dementia (FTD), another neurological disease characterized by behavioral and language changes. It’s uncertain, however, if disease is caused by reduced levels of normal C9ORF72 protein and/or by toxic RNA and proteins manufactured using instructions encoded in the extra DNA.

Jiang and colleagues will work to determine whether the loss of normal C9ORF72 protein synergizes with toxic RNA and proteins to exacerbate disease in research mouse models.

Jiang’s work may guide direction of therapy development for C9ORF72 ALS/FTD.

Funding for this MDA development grant began Feb. 1, 2017.

Eric Shoubridge, at McGill University in Montreal, Québec, was awarded an MDA research grant totaling $287,169 over three years to study a new gene linked to ALS (amyotrophic lateral sclerosis).

The recent discovery of mutations in a mitochondrial gene, CHCHD10, in patients with ALS, frontal temporal dementia (FTD) and other motor neuron diseases, implicates mitochondrial pathology as a cause of disease in some patients. CHCHD10 belongs to a family of proteins containing a specific motif that targets it to mitochondria, but its function remains almost completely unknown.

With colleagues, Shoubridge is working to elucidate the normal function of this protein and determine how mutations in it can cause ALS. The team plans to work out the basic biology of CHCHD10 in human cell culture models (muscle cells and skin cells) and to carry out the crucial experiments in motor neurons from patient-derived induced pluripotent stem cells. They will investigate the composition of CHCHD10 protein complexes, and comprehensively evaluate how mitochondrial function is altered in the face of disease-causing mutations. Finally, they will generate a zebrafish model containing ALS causative mutations, in which researchers will directly be able to evaluate the requirement of CHCHD10 for normal motor neuron function.

If successful, Shoubridge’s work could lead to important insights into the involvement of mitochondria in ALS and reveal new drug targets.

Funding for this MDA research grant began Feb. 1, 2017.

Jiou Wang, associate professor at Johns Hopkins University in Baltimore, was awarded an MDA research grant totaling $300,000 over three years to work toward a better understanding of the underlying cause of ALS (amyotrophic lateral sclerosis).

Decades of research on SOD1 and other recently discovered ALS-associated genes have revealed that increased understanding of the mechanisms of protein misfolding and quality control in neurons is a critical step toward understanding ALS and related neurodegenerative diseases, including frontotemporal dementia. Perturbation of protein quality control is a common theme in most forms of ALS, so there could be broad impact from these studies.

With colleagues, Wang will work with fly, mouse, and human stem cell models of ALS to increase understanding of how protein quality control goes awry in ALS and whether better maintenance of protein homeostasis could be a viable therapeutic avenue to explore for the disease. The team has recently identified genes that modulate specific protein quality control pathways. Now they will explore whether these pathways could yield new drug targets for ALS.

Funding for this MDA research grant began Feb. 1, 2017.