Of mice and rare neurological disease

Mice figure prominently in a pair of news items recently related to rare diseases that impact the neurology of their victims. In the case of The Jackson Laboratory (JAX) in Bar Harbor, Maine, there are two new mouse models of a disease. In the case of East Setauket, N.Y.-based Lixte Biotechnology, there's progress with a potential treatment for a disease in tests with a mouse model.

In the first case, JAX, an independent nonprofit biomedical research institute, and the Snyder-Robinson Foundation recently announced that two new mouse models are now available for the study of Snyder-Robinson syndrome (SRS) and also for broader studies of neurological development.

One of the mice is an SmsG56S CRISPR/Cas9-generated mutant of the Sms gene that carries the G56S point mutation—this strain may be useful in studies related to SRS. Meanwhile, the other mouse is an Smsflox CRISPR/Cas9-generated mutant of the Sms gene that carries a floxed exon 5. This conditional knockout strain will allow for studies at a specific stage of development in distinct tissues such as brain or muscle, while the rest of the mouse remains healthy.

SRS is an ultra-rare genetic disorder that is caused by a mutation in the SMS gene, disrupting the normal functions of the polyamine pathway. SRS is characterized by intellectual disability, seizure disorders, hypotonia, osteoporosis, gastrointestinal issues and a host of other medical problems that can be devastating. Fewer than 50 cases have been diagnosed in the United States, and fewer than one hundred cases have been diagnosed worldwide.

“We are very grateful for the tremendous contribution that Cat Lutz, Ph.D., and Aamir Zuberi, Ph.D., of The Jackson Laboratory have made to SRS research,” said Michael Raymond, executive director of the Snyder-Robinson Foundation. “We’re also very optimistic that these models will soon help researchers develop treatments for individuals struggling with SRS. This incredible gift of SRS knock-out models is especially important to our research because our community is so small, making it difficult to raise funds for research.”

In addition to developing the SRS models, Zuberi has continued to actively participate in ongoing discussion with polyamine researchers who have been exploring various ways to correct polyamine levels in the cells of SRS patients.

“The Jackson Laboratory is committed to helping families affected by all diseases—including the rarest ones—by advancing mouse model generation and therapeutic strategies to help identify causes and direct future treatments. JAX continues to work with the global scientific community to explore innovative ways to advance these efforts. We are always delighted to see the impact a single mouse model can have in moving a foundation closer to their goal,” Lutz stated.

In the second piece of news, Lixte noted that a group of neuroscientists in China and Japan reported that Lixte’s lead clinical compound, LB-100, improved muscle strength, movement coordination and learning in a mouse model of Angelman syndrome (AS), a rare disease affecting one out of 12,000 to 20,000 people in the United States.

This research reportedly involved Lixte’s proprietary compound, but Lixte and its principals are not associated with the research.

“AS patients have a constellation of signs and symptoms that may include intellectual and speech limitation, difficulty moving or balancing, frequent smiling and laughter, seizures, rigid movements, hyperactivity and sleep disorders,” explained Dr. John S. Kovach, CEO of Lixte. “Generally, there is no family history and most AS patients have a normal life span. Mice genetically modified to have reduced function of the UBE3A gene have features of human AS including movement disorder, seizure phenomena and cognitive impairment, as well as abnormalities in structural features of brain cells.

“In their publication, Wang and colleagues report that they found that brain tissue of AS mice has increased concentrations of protein phosphatase 2A (PP2A), a molecular target of Lixte’s investigational compound, LB-100. They report showing that systemic administration of LB-100 to young AS mice improved their movement disorder and the structure and function of their abnormal brain cells. This is a completely unanticipated finding. Whether LB-100 could possibly be of therapeutic benefit in AS is a question Lixte is discussing with experts in the field.”

While the new research is interesting and promising for AS, it should be noted that the focus for LB-100 has been mostly cancer-related, with the National Cancer Institute conducting a pharmacologic study to definitively determine if LB-100 enters the brain and tumor tissue in patients having surgical removal of recurrent glioblastomas

So, as Kovach noted, “Apart from the intriguing insight into a possible therapeutic approach to the symptoms of Angelman’s syndrome, Lixte is encouraged by the study of Wang and colleagues because as reported, it indicates that (some) LB-100 penetrates the brain, at least in mice with AS. In preclinical studies, LB-100 potentiates the effectiveness of standard treatments for several types of central nervous system cancers including glioblastoma multiforme, the most aggressive brain tumor of adults. However, it is not known whether LB-100 penetrates the human brain.”