Online Purchasing Account You are logged on as Guest. LoginRegister a New AccountShopping cart (Empty)
United States 

What are Disease-Modifying Therapies (DMTs)?

Rosaria Esposito
Tags: Neuroscience

When speaking about "Disease-Modifying Therapies" (DMTs), one usually refers to the medications used to treat Multiple Sclerosis (MS) patients. DMTs do not represent a cure, since they cannot revert the damage to the central nervous system (CNS) or completely stop the progression of the disease. Still, they can affect the frequency and the severity of the typical MS relapses, thus reducing the number of new lesions, delaying the onset of significant disabilities, and extending survival. This is the short and simple version of the question asked in the title. If you are still curious and would like to know a bit more about MS, the different types of DMTs, and their working principles… Then keep reading!


Background information about Multiple Sclerosis

According to the last report of the Multiple Sclerosis International Federation (MSIF), a total of 2.8 million people were estimated to live in 2020 with MS worldwide (35.9 per 100,000 population), with women twice more likely than men to develop this condition (1). Multiple Sclerosis represents, therefore, the most common non-traumatic disabling disease affecting young adults (2).
From a biological point of view, MS is a chronic inflammatory disorder of the CNS (brain and spinal cord), characterized by the disruption of the myelin sheath protecting the nerve fibers (demyelination), local inflammation, and ultimately neuronal damage. This degenerative process is presumably linked to an autoimmune pathogenesis, and more specifically, to a T cell-mediated inflammatory disorder. In addition, recent evidence, based on the success of some B cell-depleting therapies, indicates the role of other bone marrow-derived immune cells in the pathogenesis of the disease (3).
From a clinical point of view, MS can be categorized into four types (4):
  • Clinically Isolated Syndrome (CIS): corresponds to the first episode of neurological symptoms lasting at least 24 hours and suggestive of MS.
  • Relapsing-Remitting MS (RRMS): this is the most common first diagnosis of MS (85% of patients). It is characterized by relapsing-remitting cycles of symptoms. A relapse is defined by the appearance of new symptoms or the return of past symptoms, typically lasting from a few days to a few weeks. Relapses are caused by the immune system launching an inflammatory attack against nerve fibres. During attacks, new parts of the nervous system can become damaged, leading to new symptoms that can therefore vary, depending on which parts of the nervous system are most affected. The subsequent remission phase is characterized by repair and compensation mechanisms that can initially ease or eliminate symptoms, until the underlying neuronal damage becomes increasingly evident, and patients typically show a progressive decline.
  • Secondary Progressive MS (SPMS): this stage often follows the previous one, and is the second largest category of MS. In this phase, the symptoms steadily worsen over time. There might be slight, less dramatic relapses, but the symptoms do not disappear in the remission phase.
  • Primary Progressive MS (PPMS): it affects approximately 15% of MS patients. Unlike previous cases, PPMS progresses steadily from the onset, without relapsing-remitting cycles. In addition, PPMS is characterized by lower inflammatory levels, and the lesions tend to concentrate in the spinal cord more than in the brain.
Unfortunately, the etiopathogenesis of MS, probably responsible also for its different clinical manifestations, is still unclear, but certainly very complex. We know that both genetic predisposition and environmental influences are related to the risk of developing MS. Studies conducted on northern European monozygotic twins demonstrated a concordance rate of MS between 20-30% (in the general population, this rate is only 0.1-0.2%). This suggests, on the one hand, a high degree of heritability and, on the other, that non-mendelian factors also contribute to the development of the disease (i.e. epigenetic regulation, environmental factors) (5).
As for the genetic risk, it has been known for a few years that several variants of HLA antigen affect the risk of developing MS (5,6). In addition, in the past 15 years, large international collaborative studies allowed to associate hundreds of susceptibility variants to MS development, often located in the non-coding regions of the genome but close to genes that regulate innate or adaptive immunity, also shared by several other autoimmune diseases (5). Concerning the environmental factors whose correlation with MS development is pretty well ascertained, it is worth mentioning Epstein Barr Virus infection, low sunlight exposure and vitamin deficiency, obesity and dietary habits, and finally, smoking (5).


Examples of Disease-Modifying Therapies

Despite the scientific community's efforts, a definitive cure for Multiple Sclerosis is yet to be found. However, a number of Disease-Modifying Therapies (DMTs) are routinely used, often considerably improving the quality of MS patients' life. Because of the inflammatory autoimmune nature of MS, DMTs typically target the immune response by modulating lymphocytes number, proliferation and trafficking, or cytokine production. It is worth highlighting here that the majority of DMTs are effective only on the relapsing form of the disease, probably because the primary progressive forms of MS are less associated with inflammation, and are therefore less responsive to this kind of approach. Table 1 lists a few examples of licenced DMTs for Multiple Sclerosis, with their proposed mechanisms of action (information is summarized in ref. 7 and 8).
Since curative treatments are not available, these therapies aim mainly to decrease the risk of relapses and disability progression by reducing the appearance of new lesions in the CNS. Currently available DMTs are commonly distinguished as moderate-efficacy (e.g. interferon-beta, glatiramer acetate) and high-efficacy DMTs.
The moderate efficacy DMTs are characterized by a well-defined safety profile. In contrast, the high efficacy ones (usually newer and therefore less known) carry a higher risk of serious side effects. For this reason, a common strategy included in medical guidelines is the "escalation approach" (9): moderate-efficacy therapies are the "first line", whereas it is advised to use the high-risk treatments only in highly active disease or in case of failure of the first line.
More recently, an increasing number of studies are highlighting the importance of early intervention with high-efficacy treatments as the best window of opportunity to delay irreversible CNS damage and disability progression. The benefit/risk ratio also seems to be more positive, as information on the long-term safety risks is more and more available (10). The use of more effective medications from the onset of MS diagnosis could therefore be introduced in clinical guidelines in the near future, thereby increasing the options of therapies available.

Never miss a new TechNote!

Receive our TechNotes as soon as they are published.


Follow Us!

 

TARGET

NAME

PROPOSED MECHANISM OF ACTION

EFFECTS AND CLASSIFICATION

Lymphocyte number

Alemtuzumab

Monoclonal Ab binding CD52 on T and B cells, resulting in their depletion and subsequent slow repopulation.

Reduces the number of relapses in RRMS patients. Classified as “high efficacy”.

Ocrelizumab

Recombinant Ab against CD20, expressed on B cells causing their depletion.

Reduces relapses; reduces disability progression; reduces number of lesions shown on MRI. Only drug licensed for PPMS. Classified as “high efficacy”.

Lymphocyte proliferation

Cladribine

Interferes with DNA synthesis and repair of T and B cells, depleting them.

Reduces relapses rate; reduces disability progression; reduces loss of brain cells. Classified as “high efficacy”.

Teriflunomide

Pyrimidine synthesis inhibitor. Inhibits cell proliferation. Immunomodulatory effect probably mediated by the reduction of lymphocyte number.

Reduces relapses; disability progression. Classified as “moderate efficacy”.

Lymphocyte trafficking

Fingolimod

Sphingosine-1-receptor modulator; sequesters lymphocytes and decreasing T cell infiltration into the CNS.

Reduces relapses. Classified as “high efficacy”.

Natalizumab

Monoclonal Ab acting as an α4-integrin receptor antagonist; decreases T cell migration across the blood-brain barrier, thus reducing CNS inflammation.

Reduces relapses; reduces MS lesions; reduces disability progression. Classified as “high efficacy”.

Cytokine production

Interferon beta

Reduces pro-inflammatory cytokines release; down-regulates antigen presentation; inhibits lymphocytes migration into CNS.

Reduces relapses. Classified as “moderate efficacy”.

Glatiramer acetate

Synthetic peptides (4-amino acid long) resembling myelin basic protein (MBP). Strong promiscuous binding to MHC molecules and inhibits T cell response to several myelin antigens.

Reduces relapses. Classified as “moderate efficacy”.


Table 1. Examples of licenced disease-modifying therapies for Multiple Sclerosis


Neurosciences at Enzo

At Enzo, we believe in providing scientists with novel tools that will help your research on neurodegenerative diseases and their cellular basis, contributing to developing increasingly effective therapies. Our comprehensive portfolio for Neuroscience research ranges from relevant biomarkers to tools to investigate altered cellular processes (Figure 1).
 
Enzo tools for your studies on neurodegenerative disease

Figure 1. Overview of Enzo tools for your studies on neurodegenerative disease.


For example, in a recent article published in Nature neurosciences, a German group demonstrated that neuroinflammation leads to toxic protein accumulation in the neuronal somata of mice and patients with MS, thus suggesting proteasome activation as a potential remedy. Two of the most popular products in our neurosciences catalogue have been instrumental in this work: PROTEOSTAT® Aggresome detection kit and Bassoon monoclonal antibody (SAP7F407).

Do you have questions about the available tools for your research? Do you need help in setting up your experiment? Want to learn more about our portfolio? Do not hesitate to reach out to our Technical Support Team. We will be happy to assist!
 

Did you enjoy the reading?
Share it on your favorite social media

 
comments powered by Disqus

References:

  1. Walton C, et al. Rising prevalence of Multiple Sclerosis worldwide: Insights from the Atlas of MS, third edition. Mult. Scler. (2020). PMID: 33174475.
  2. Dobson R & Giovannoni G. Multiple sclerosis – a review. Mult. Scler. (2017). PMID: 30300457.
  3. Manouchehri N, et al. Efficacy of Disease Modifying Therapies in Progressive MS and How Immune Senescence May Explain Their Failure. Front. Neurol. (2022). PMID: 35432156.
  4. Wexler M. Disease-modifying Therapies for Multiple Sclerosis. Multiple Sclerosis News Today.
  5. Nourbakhsh B & Mowry EM. Multiple Sclerosis Risk Factors and Pathogenesis. Continuum (Minneap Minn) (2019). PMID: 31162307.
  6. Moutsianas L, Jostins L, Beecham AH, et al. Class II HLA interactions modulate genetic risk for Multiple Sclerosis. Nat. Genet. (2015). PMID: 26343388.
  7. De Angelis F et al. Disease-modifying therapies for Multiple Sclerosis. BMJ (2018). PMID: 30482751.
  8. MS-UK. Supporting Your MS journey: Disease modifying therapies.
  9. Ontaneda D et al. Early highly effective versus escalation treatment approaches in relapsing Multiple Sclerosis. Lancet Neurol. (2019). PMID: 31375366.
  10. Filippi M, et al. Early use of high-efficacy disease‑modifying therapies makes the difference in people with Multiple Sclerosis: an expert opinion. J. Neurol. (2022). PMID: 35608658.
  11. Shattling B et al. Bassoon proteinopathy drives neurodegeneration in Multiple Sclerosis. Nat. Neurosci. (2019). PMID: 31011226.

Featured Products

PROTEOSTAT® Aggresome detection kit  

Robust, quantitative detection of aggresomes relevant to the study of neurodegenerative disease, liver disease and  toxicology
Flow Cytometry, Fluorescence microscopy, Fluorescent detection | Print as PDF
 
ENZ-51035-0025 25 tests 129.00 USD
 
ENZ-51035-K100 100 tests 372.00 USD
Do you need bulk/larger quantities?
 

CYTO-ID® Autophagy detection kit 2.0 

A brighter and more photostable, no-transfection, quantitative assay for monitoring autophagy in live  cells
Flow Cytometry, Fluorescence microscopy, Fluorescent detection, HTS | Print as PDF
 
ENZ-KIT175-0050 50 tests 259.00 USD
 
ENZ-KIT175-0200 200 tests 548.00 USD
Do you need bulk/larger quantities?
 

Bassoon monoclonal antibody (SAP7F407) 

Purified from ascites., ICC, IF, IHC, IP, WB | Print as PDF
 
ADI-VAM-PS003-D 50 µg 249.00 USD
 
ADI-VAM-PS003-F 200 µg 525.00 USD
Do you need bulk/larger quantities?
 

Bassoon monoclonal antibody (SAP7F407) 

Purified from hybridoma tissue culture supernatant., ICC, IF, IHC, IP, WB | Print as PDF
 
ENZ-ABS666-0050 50 µg 312.00 USD
 
ENZ-ABS666-0200 200 µg 662.00 USD
Do you need bulk/larger quantities?
 

C-reactive protein (human), (recombinant) 

Produced in HEK 293 cells., ≥95% (SDS-PAGE) | Print as PDF
 
ENZ-PRT164-0100 100 µg 221.00 USD
Do you need bulk/larger quantities?
 

CRP (human) ELISA kit 

Sensitive (8.876 ng/ml) ELISA kit for the quantification of CRP, an early biomarker for inflammation
ELISA, Colorimetric detection | Print as PDF
 
ENZ-KIT102-0001 96 wells 351.00 USD
Do you need bulk/larger quantities?
 

IL-1β (human), ELISA kit 

ELISA, Colorimetric detection | Print as PDF
 
ADI-900-130A 96 wells 650.00 USD
Do you need bulk/larger quantities?
 

IL-6 (human), high sensitivity ELISA kit 

Most sensitive (0.057 pg/mL) colorimetric kit for IL-6 quantification
ELISA, Colorimetric detection | Print as PDF
 
ENZ-KIT178-0001 96 wells 590.00 USD
Do you need bulk/larger quantities?
 

TNF-α (human), ELISA kit 

Highly sensitive ELISA for measuring TNF-α, the primary mediator of immune regulation.
ELISA, Colorimetric detection | Print as PDF
 
ADI-900-099 96 wells 557.00 USD
Do you need bulk/larger quantities?
 

ROS-ID® Total ROS detection kit 

Flow Cytometry, Fluorescence microscopy, Fluorescent detection, HTS | Print as PDF
 
ENZ-51011 1 Kit 200.00 USD
Do you need bulk/larger quantities?
 

GFP-CERTIFIED® FLUOFORTE® Calcium assay kit 

A brighter, more robust and GFP-compatible (orange dye) fluorescent assay for calcium mobilization
Flow Cytometry, Fluorescence microscopy, Fluorescent detection, HTS | Print as PDF
 
ENZ-51020-KP010 10x96 wells 529.00 USD
 
ENZ-51020-KP100 100x96 wells 3,711.00 USD
Do you need bulk/larger quantities?
 

Recommend this page