The sphingosine 1-phosphate (S1P) signalling pathways have important and diverse functions. S1P receptors (S1PRs) have been proposed as a therapeutic target for various diseases due to their ...involvement in regulation of lymphocyte trafficking, brain and cardiac function, vascular permeability, and vascular and bronchial tone. S1PR modulators were first developed to prevent rejection by the immune system following renal transplantation, but the only currently approved indication is multiple sclerosis. The primary mechanism of action of S1PR modulators in multiple sclerosis is through binding S1PR subtype 1 on lymphocytes resulting in internalisation of the receptor and loss of responsiveness to the S1P gradient that drives lymphocyte egress from lymph nodes. The reduction in circulating lymphocytes presumably limits inflammatory cell migration into the CNS. Four S1PR modulators (fingolimod, siponimod, ozanimod, and ponesimod) have regulatory approval for multiple sclerosis. Preclinical evidence and ongoing and completed clinical trials support development of S1PR modulators for other therapeutic indications.
Until recently, all approved multiple sclerosis (MS) disease treatments were administered parenterally. Oral fingolimod was approved in September 2010 by the US Food and Drug Administration to reduce ...relapses and disability progression in relapsing forms of MS. In the clinical trials that led to approval, fingolimod reduced not only acute relapses and magnetic resonance imaging lesion activity but also disability progression and brain volume loss, suggesting preservation of tissue. Fingolimod's mechanism of action in MS is not known with certainty. Its active form, fingolimod‐phosphate (fingolimod‐P), is a sphingosine 1‐phosphate receptor (S1PR) modulator that inhibits egress of lymphocytes from lymph nodes and their recirculation, potentially reducing trafficking of pathogenic cells into the central nervous system (CNS). Fingolimod also readily penetrates the CNS, and fingolimod‐P formed in situ may have direct effects on neural cells. Fingolimod potently inhibits the MS animal model, experimental autoimmune encephalomyelitis, but is ineffective in mice with selective deficiency of the S1P1 S1PR subtype on astrocytes despite normal expression in the immune compartment. These findings suggest that S1PR modulation by fingolimod in both the immune system and CNS, producing a combination of beneficial anti‐inflammatory and possibly neuroprotective/reparative effects, may contribute to its efficacy in MS. In clinical trials, fingolimod was generally safe and well tolerated. Its interaction with S1PRs in a variety of tissues largely accounts for the reported adverse effects, which were seen more frequently with doses 2.5 to 10× the approved 0.5mg dose. Fingolimod's unique mechanism of action distinguishes it from all other currently approved MS therapies. Ann Neurol 2011;69:759–777
Summary Multiple sclerosis is a major cause of neurological disability, which accrues predominantly during progressive forms of the disease. Although development of multifocal inflammatory lesions is ...the underlying pathological process in relapsing-remitting multiple sclerosis, the gradual accumulation of disability that characterises progressive multiple sclerosis seems to result more from diffuse immune mechanisms and neurodegeneration. As a result, the 14 anti-inflammatory drugs that have regulatory approval for treatment of relapsing-remitting multiple sclerosis have little or no efficacy in progressive multiple sclerosis without inflammatory lesion activity. Effective therapies for progressive multiple sclerosis that prevent worsening, reverse damage, and restore function are a major unmet need. In this Series paper we summarise the current status of therapy for progressive multiple sclerosis and outline prospects for the future.
Abstract Mesenchymal stem cells (MSCs) are pluripotent non-hematopoietic precursor cells that can be isolated from bone marrow and numerous other tissues, culture-expanded to purity, and induced to ...differentiate in vitro and in vivo into mesodermal derivatives. MSCs exhibit many phenotypic and functional similarities to pericytes. The immunomodulatory, tissue protective, and repair-promoting properties of MSCs demonstrated both in vitro and in animal models make them an attractive potential therapy for MS and other conditions characterized by inflammation and/or tissue injury. Other potential advantages of MSCs as a therapeutic include the relative ease of culture expansion, relative immunoprivilege allowing allogeneic transplantation, and their ability to traffic from blood to areas of tissue allowing intravascular administration. The overall published experience with MSC transplantation in MS is modest, but several small case series and preliminary studies yielded promising results. Several groups, including us, recently initiated formal studies of autologous, culture-expanded, bone marrow-derived MSC transplantation in MS. Although there are several potential safety concerns, to date, the procedure has been well tolerated. Future studies that more definitively assess efficacy also will need to address several technical issues.
Hot Topics in Tetralogy of Fallot Villafañe, Juan, MD; Feinstein, Jeffrey A., MD; Jenkins, Kathy J., MD, MPH ...
Journal of the American College of Cardiology,
12/2013, Letnik:
62, Številka:
23
Journal Article
Recenzirano
Odprti dostop
Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart defect. We explore “hot topics” to highlight areas of emerging science for clinicians and scientists in moving toward a better ...understanding of the long-term management of patients with repaired TOF. From a genetic perspective, the etiology of TOF is multifactorial, with a familial recurrence risk of 3%. Cardiac magnetic resonance is the gold standard assessment tool based on its superior imaging of the right ventricular (RV) outflow tract, pulmonary arteries, aorta, and aortopulmonary collaterals, and on its ability to quantify biventricular size and function, pulmonary regurgitation (PR), and myocardial viability. Atrial re-entrant tachycardia will develop in more than 30% of patients, and high-grade ventricular arrhythmias will be seen in about 10% of patients. The overall incidence of sudden cardiac death is estimated at 0.2%/yr. Risk stratification, even with electrophysiologic testing and cardiac magnetic resonance, remains imperfect. Drug therapy has largely been abandoned, and defibrillator placement, despite its high risks for complications and inappropriate discharges, is often recommended for patients at higher risk. Definitive information about optimal surgical strategies for primary repair to preserve RV function, reduce arrhythmia, and optimize functional status is lacking. Post-operative lesions are often amenable to transcatheter intervention. In selected cases, PR may be treated with transcatheter valve insertion. Ongoing surveillance of RV function is a crucial component of clinical assessment. Except for resynchronization with biventricular pacing, no medical therapies have been shown to be effective after RV dysfunction occurs. In patients with significant PR with RV dilation, optimal timing of pulmonary valve replacement remains uncertain, although accepted criteria are emerging.
Sphingosine 1-phosphate receptor (S1PR) modulators possess a unique mechanism of action in the treatment of multiple sclerosis (MS). Subtype 1 of the S1PR is expressed on the surface of lymphocytes ...and is important in regulating egression from lymph nodes. The S1PR modulators indirectly antagonize the receptor’s function leading to sequestration of lymphocytes in the lymph nodes. Fingolimod was the first S1PR modulator to receive regulatory approval for relapsing-remitting MS after 2 phase III trials demonstrated potent efficacy, safety, and tolerability. Fingolimod can cause undesirable effects as a result of its interaction with other S1PR subtypes, which are expressed in diverse tissues, including cardiac myocytes. As such, agents that more selectively target subtype 1 of the S1PR are of interest and are at various stages of development. These include ponesimod (ACT128800), siponimod (BAF312), ozanimod (RPC1063), ceralifimod (ONO-4641), GSK2018682, and MT-1303. Data from phase II trials and early results from phase III studies have been promising and will be presented in this review. Of special interest are results from the EXPAND study of siponimod, which suggest a potential role for S1PR modulators in secondary progressive MS.
Sphingosine 1-phosphate (S1P) receptor modulators possess a unique mechanism of action as disease-modifying therapy for multiple sclerosis (MS). Subtype 1 S1P receptors are expressed on the surfaces ...of lymphocytes and are important in regulating egression from lymph nodes. The S1P receptor modulators indirectly antagonize the receptor's function and sequester lymphocytes in lymph nodes. Fingolimod was the first S1P agent approved in the USA in 2010 for relapsing MS after two phase III trials (FREEDOMS and TRANSFORMS) demonstrated potent efficacy, and good safety and tolerability. Post-marketing experience, as well as a third phase III trial (FREEDOMS II), also showed favorable results. More selective S1P receptor agents-ponesimod (ACT128800), siponimod (BAF312), ozanimod (RPC1063), ceralifimod (ONO-4641), GSK2018682, and MT-1303-are still in relatively early stages of development, but phase I and II trials showed promising efficacy and safety. However, these observations have yet to be reproduced in phase III clinical trials.
Oral treatment options for disease-modifying therapy in relapsing multiple sclerosis have substantially increased over the past decade with four approved oral compounds now available: fingolimod, ...dimethyl fumarate, teriflunomide, and cladribine. Although these immunomodulating therapies are all orally administered, and thus convenient for patients, they have different modes of action. These distinct mechanisms of action allow better adaption of treatments according to individual comorbidities and offer different mechanisms of treatment such as inhibition of immune cell trafficking versus immune cell depletion, thereby substantially expanding the available treatment options.
New sphingosine-1-phosphate receptor (S1PR) modulators with more specific S1PR target profiles and potentially better safety profiles compared with fingolimod were tested in patients with relapsing multiple sclerosis. For example, siponimod, which targets S1PR1 and S1PR5, was approved in March, 2019, by the US Food and Drug Administration for the treatment of relapsing multiple sclerosis including active secondary progressive multiple sclerosis. Ozanimod, another S1P receptor modulator in the approval stage that also targets S1PR1 and S1PR5, reduced relapse rates and MRI activity in two phase 3 trials of patients with relapsing multiple sclerosis. Blocking of matrix metalloproteinases or tyrosine kinases are novel modes of action in the treatment of relapsing multiple sclerosis, which are exhibited by minocycline and evobrutinib, respectively. Minocycline reduced conversion to multiple sclerosis in patients with a clinically isolated syndrome. Evobrutinib reduced MRI activity in a phase 2 trial, and a phase 3 trial is underway, in patients with relapsing multiple sclerosis. Diroximel fumarate is metabolised to monomethyl fumarate, the active metabolite of dimethyl fumarate, reduces circulating lymphocytes and modifies the activation profile of monocytes, and is being tested in this disease with the aim to improve gastrointestinal tolerability. The oral immunomodulator laquinimod did not reach the primary endpoint of reduction in confirmed disability progression in a phase 3 trial of patients with relapsing multiple sclerosis. In a phase 2 trial of patients with primary progressive multiple sclerosis, laquinimod also did not reach the primary endpoint of a reduction in brain volume loss, as a consequence the development of this drug will probably not be continued in multiple sclerosis.
Several new oral compounds are in late-stage clinical development. With new modes of action introduced to the treatment of multiple sclerosis, the question of how to select and sequence different treatments in individual patients arises. Balancing risks with the expected efficacy of disease-modifying therapies will still be key for treatment selection. However, risks as well as efficacy can change when moving from the controlled clinical trial setting to clinical practice. Because some oral treatments, such as cladribine, have long-lasting effects on the immune system, the cumulative effects of sequential monotherapies can resemble the effects of a concurrent combination therapy. This treatment scheme might lead to higher efficacy but also to new safety concerns. These sequential treatments were largely excluded in phase 2 and 3 trials; therefore, monitoring both short-term and long-term effects of sequential disease-modifying therapies in phase 4 studies, cohort studies, and registries will be necessary.
PDF
