Experimental drug reverses multiple sclerosis damage in mouse model

A drug developed by a UVA Health scientist has not only stopped but reversed paralysis and vision loss in a mouse model of multiple sclerosis. The results are striking because existing MS treatments are designed to reduce future inflammatory attacks, not restore neurological function already lost. 

The drug, Kamuvudine K-9, is a derivative of HIV drugs already approved for use in people. It was developed by Jayakrishna Ambati, MD, founding director of UVA's Center for Advanced Vision Science and the DuPont Guerry III Professor in the UVA School of Medicine's Department of Ophthalmology.

In Ambati's new lab results, K-9 preserved nerve fibers and their myelin insulation that MS destroys. The drug also halted the rise in neurofilament light chain (NfL), a blood biomarker of nerve damage. In the same experiments, animals treated with an approved MS drug did not recover nearly as much function as those receiving K-9.

Ambati said the case for the therapeutic potential of K-9 is bolstered by the apparent MS protection offered by the HIV drugs K-9 is derived from, called nucleoside/nucleotide reverse transcriptase inhibitors, or NRTIs. NRTI use in patients, Ambati's team reports in a new paper, is associated with a 41% reduction in the risk of developing MS and a 36% reduction in the annual relapse rate among patients with MS. The researchers drew this conclusion based on an analysis of health insurance data from more than 3 million people.

Most MS therapies are aimed at preventing the next attack. What's remarkable is that K-9 not only prevented further neurological deterioration, but animals recovered function they had already lost. When that recovery is considered together with the preservation of nerve tissue, the NfL response and the human epidemiologic findings, we believe there is a compelling rationale to test this approach in patients."

Jayakrishna Ambati, MD, founding director of UVA's Center for Advanced Vision Science and the DuPont Guerry III Professor in the UVA School of Medicine's Department of Ophthalmology

Stopping multiple sclerosis

MS is the most common disabling neurological disease among young adults and affects nearly a million Americans. It typically appears between ages 20 and 40. Initial symptoms often include vision loss and extreme fatigue, then can progress to weakness and difficulty moving. In severe cases, life-threatening complications can develop. The progression of the disease, however, can vary greatly from patient to patient. Some people enjoy long periods of remission, and doctors categorize the disease based on each patient's symptoms and relapses. 

On average, patients with MS live 7 years less than people who do not have the autoimmune disorder. Existing medicines can slow the disease's progression and reduce the number of flareups, but there is no cure. While the available drugs are beneficial, MS still can take a tremendous toll on patients' quality of life, so new and better treatments are greatly needed.

MS is thought to develop when our immune cells begin attacking the myelin sheaths that insulate our nerves. This harmful inflammation ultimately disrupts the communication between the brain and the body. 

Ambati discovered, however, that NRTIs can block an important inflammation pathway called inflammasome activation. That prompted him to develop K-9 as an alternative to NRTIs that appears safer and even more effective.

K-9 has already entered clinical trials in eye diseases, including diabetic macular edema and thyroid eye disease. That existing clinical experience could help accelerate evaluation of K-9 in MS.

The researchers emphasize that K-9 remains experimental for MS and that controlled clinical trials will be required to determine whether the recovery seen in mice can translate to people. They hope the work will also inform studies of other neurodegenerative diseases in which inflammasome activation and axonal injury are implicated, including amyotrophic lateral sclerosis (ALS), in which K-9 is slated to be tested.

"Inflammasome inhibition is now recognized as the cutting edge of therapies for multiple inflammatory diseases," Ambati said. "K-9 and the related K-8, which has already shown remarkable efficacy in macular degeneration, could also be beneficial in other diseases such as Alzheimer's disease and Parkinson's disease."

Accelerating the development of new drugs and treatments for the most complex diseases is the cornerstone mission of UVA's new Paul and Diane Manning Institute of Biotechnology. The institute's efforts to more quickly translate UVA's cutting-edge science into lifesaving and life-changing treatments is being complemented by the launch of a statewide clinical trials network that will provide Virginians access to the testing of these potential treatments as they are being developed.

A 350,000-square foot home for the institute is under construction in UVA's Fontaine Research Park.

Findings published

Ambati and his team published their new MS findings in the scientific journal Science Translational Medicine. The research team consisted of Praveen Yerramothu, Kameshwari Ambati, Joseph Magagnoli, Meenakshi Ambati, Thendral Velmurugan, Dijing Yu, Jing Zhang, Jingjing Zhang, Tammy Cummings, Joseph Nguyen, Claire C. Thomas, Vidya L. Ambati, Kaitlyn Cheng, Maksud Juraev, Roshni Dholkawala, Felipe Pereira, Peirong Huang, Ayami Nagasaka, Yosuke Nagasaka, Madhuri Rudraraju, Ashley Ban, Ivana Apicella, Xiaoyu Cai, Ranjith Konduri, Rhea Zahir, Elizabeth Frost, John Lukens, Ruwen Yin, Frederick Brøndsted, Cliff I. Stains, Makoto Ono, Brian P. Delisle, Jamie Horn, Markos Leggas, Jeffrey L. Dupree, S. Scott Sutton, Bradley D. Gelfand, Shao-bin Wang and Jayakrishna Ambati.

Jayakrishna Ambati is co-founder of Inflammasome Therapeutics and iVeena Delivery Systems.