A new National Institutes of Health (NIH)-funded study has found that the experimental drug kamuvudine-9 (K-9) may help reverse pre-existing vision loss and paralysis in animal models of Multiple Sclerosis (MS). Researchers at the University of Virginia reported that K-9’s effects were likely linked to its ability to prevent activation of the inflammasome, a cell-killing immune mechanism in the brain and spinal cord.

The findings were supported by a nationwide analysis of insurance claims involving more than 3 million patients. The analysis found lower rates of MS diagnosis and relapses among patients receiving Nucleoside Reverse Transcriptase Inhibitors (NRTIs), a class of antiviral medicines that includes compounds from which K-9 was developed.

Michael F. Chiang, Director of NIH’s National Eye Institute (NEI), said the reversal of severe MS-related complications observed in animals, together with K-9’s safety profile, could support further research into its potential clinical application.

MS-related neurodegeneration has traditionally been associated with the adaptive immune system, in which B and T cells mistakenly attack healthy tissue. Existing MS treatments largely target these immune responses and can reduce relapses, but they do not generally reverse damage that has already occurred and may broadly suppress immune function.

Recent research has suggested that adaptive immune activity could instead act as an upstream trigger for the inflammasome, a component of the central nervous system’s innate immune system. Once activated, the inflammasome can initiate processes that lead to extensive cell death and neurodegeneration.

NRTIs are antiviral drugs approved for conditions including HIV and hepatitis B. Researchers at the University of Virginia, led by Jayakrishna Ambati, modified these compounds to remove their antiviral activity while retaining their ability to inhibit inflammasome activation. The resulting compounds were designed to avoid neurological and muscular side effects associated with long-term use of some NRTIs.

The team had previously reported that K-9 could prevent retinal damage and preserve vision in animal models of retinal detachment. In the latest study, researchers examined whether the compound could produce similar protective effects in MS, where vision impairment is a common symptom.

Researchers induced an MS-like condition in mice and began administering K-9 after neurological symptoms became visibly apparent. Treatment continued for two weeks. The animals receiving K-9 were protected from further neurological deficits and showed recovery from previously observed motor impairment and vision loss. The researchers reported that the recovery was greater than that observed in the other treatment groups, including animals receiving a standard MS drug.

Further analysis indicated that K-9 helped protect axons and their myelin sheaths, which are essential for transmitting signals through the central nervous system. The treated animals also showed lower levels of Neurofilament Light chain (NfL), a blood-based biomarker associated with nerve damage and one that has previously been used by the US Food and Drug Administration (FDA) in the development and approval of certain treatments for neurodegenerative conditions.

The researchers linked K-9’s effects to the suppression of two separate pathways involved in inflammasome activation. These findings suggest that targeting inflammasome activity could offer a different approach to addressing the neurodegenerative processes associated with MS.

To complement the animal experiments, the researchers analysed insurance claims from three US patient populations, including individuals receiving NRTIs for HIV or hepatitis B. Patients taking NRTIs had lower rates of MS diagnosis compared with those who were not receiving the medicines. Among patients already diagnosed with MS, NRTI use was also associated with fewer subsequent relapses.

Ambati said that although NRTIs are chemically different from K-9, their ability to inhibit inflammasome activation provides a human-data signal consistent with the mechanism observed in the K-9 studies.

K-9 has previously been evaluated in clinical trials for eye conditions including diabetic macular edema and thyroid eye disease. A related compound, kamuvudine-8 (K-8), has also shown potential in research involving late-stage macular degeneration. The researchers plan to advance K-9 toward clinical studies in MS and potentially other neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS).

The research was supported by multiple NIH grants through the National Eye Institute, National Institute on Aging, National Institute on Drug Abuse and National Institute of General Medical Sciences.

The NEI is the federal agency responsible for conducting and supporting research on the visual system and eye diseases, including basic and clinical research aimed at developing treatments for vision loss. NIH, part of the US Department of Health and Human Services, is the US government’s primary agency for biomedical and public health research and comprises 27 institutes and centres.