Background

Multiple sclerosis (MS) is a chronic immune-mediated condition of the central nervous system (CNS) that manifests as demyelination and neurodegeneration resulting in neurological impairments. MS is most often diagnosed in young adults between 20 and 49 years old who live with the debilitating consequences of the disease for decades. Approximately 85% of MS individuals initially present with a relapsing–remitting form of the disease (RRMS), with most advancing to secondary progressive MS (SPMS) within 15–20 years. In MS disease course, clinically isolated syndrome (CIS) describes an individual who presents with a first episode of neurological dysfunction characterized by demyelination or inflammation in the CNS consistent with an MS relapse.

When accompanied by brain lesions suggestive of MS on magnetic resonance imaging (MRI), CIS indicates a high probability of a future MS diagnosis. Unfortunately, current clinical MS assessments lack sensitivity for early diagnosis and prediction of disease progression because they most commonly rely on a combination of MRI detection of demyelinating plaques combined with a clinical presentation. As such, there is a need for identification of early disease biomarkers to facilitate MS diagnosis and preventive treatments.

Moreover, most currently available MS therapies are immunosuppressive, increase the risk of systemic infections and comorbidities while not addressing the neurodegenerative aspect of disease. Thus, there is a critical need to identify endogenous mechanisms that drive disease progression and pinpoint new disease markers for early diagnosis and treatment of progressive MS.

Technology Overview

Researchers at The University of Manitoba have identified an endogenous pathway that appears to play a key role in the development of MS pathogenesis and may allow for the development of novel markers for early diagnosis, disease prevention and personalized therapeutic approaches.

Utilizing MS patient samples and a preclinical mouse model, researchers have discovered that a decline in the plasma levels of the signalling protein Nrg-1b1 is positively associated with MS development and progression, and could be potentially used as an early disease marker to help in MS diagnosis. Researchers found that plasma levels of Nrg-1b1 were lower in patients with clinically isolated syndrome (CIS) at the onset of the disease compared to healthy individuals and were associated with the subsequent diagnosis of definitive MS (Fig. A). Similarly, in a mouse model of experimental autoimmune encephalomyelitis (EAE), downregulation of Nrg-1b1 was detected at non-symptomatic phase and during EAE onset in the plasma and spleen and within the EAE lesions in the central nervous system (CNS).

Importantly, dysregulation of Nrg-1b1 appeared to functionally impact EAE progression, as restoring its deficient levels in mice through systemic administration was effective to delay EAE symptoms and ameliorate disease severity. Mechanistically, the comprehensive analyses have identified an immune modulatory role for Nrg-1b1 that appeared to be primarily through modulation of innate immune response in EAE (Fig. B).

Stage of Development:

• TRL3

Benefits

The evidence highlights the potential of Nrg-1b1 as an early disease biomarker and a promising therapeutic target in MS. Firstly, this treatment is aimed to restore the dysregulated levels of endogenous Nrg-1b1. Secondly, Nrg-1b1 regulates the phenotype of innate and adaptive immune cells rather than suppressing the immune response.

Nrg-1b1 treatment offers an extended therapeutic time window by showing efficacy when administered at various points during the course of the disease. It potentially addresses multiple aspects of MS including attenuation of the severity of the disease symptoms, being effective when administered prophylactically, symptomatically as well as chronically during the disease progression.

Lastly, an important characteristic of Nrg-1b1 peptide is its desirable pharmacokinetics for CNS therapeutics, as its ability to pass the blood-CNS barrier is confirmed. In fact, a clinical grade of this peptide has moved to Phase II/III clinical trials for chronic cardiac failure, indicating its safety. Taken together, the work in a disease relevant mode of MS indicates that Nrg-1 treatment is able to confer immunomodulatory, neuroprotective and neuroregenerative effects, which makes it a promising multifaceted therapeutic drug target in MS with the potential to treat MS at various stages of the disease.

Applications

While Nrg1-β1 blood levels can serve as biomarker for early detection of MS, Nrg1-β1 therapy could be used as a therapeutic treatment for MS and potentially other autoimmune diseases and demyelinating disorders.

Opportunity

The University is actively seeking a licensee to license the patent to move this technology to market. The University also welcomes interactions with any investor or entrepreneur that would like to license the patent to create a start‑up based in Manitoba, or outside of the province.

The University would also welcome a company to invest in this research in Sponsored Research to further validate the utility of Nrg1-β1 as a biomarker and the Nrg1-β1 peptide as a clinically relevant therapeutic.