Gene Therapy In Experimental AutoImmune EncephaloMyelitis
Mathisen PM, Tuohy VK
J Clin Immunol 2000 Sep;20(5):327-33
Lerner Research Institute, Dept of Immunology, and
The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA
PMID# 11051274; UI# 20503570
Gene therapy traditionally has been associated with "gene replacement." where exogenous recombinant DNA is introduced ex vivo into Somatic Cells that are then introduced back into the patient as a way to correct an inherited Genetic defect.
However, several novel Gene therapy strategies for treating AutoImmune Diseases recently have emerged.
Strategies involving the use of several types of DNA vaccines, the application of various Viral vectors, and the use of diverse cellular vectors have shown promise in inhibiting AutoImmune-mediated inflammation and repairing tissue damaged as a result of AutoImmune attack.
In the current review, we examine and discuss the development and proposed use of emerging Gene therapy strategies for the treatment of AutoImmune Disease.
With specific emphasis on Experimental AutoImmune EncephaloMyelitis (EAE), an animal model widely used in Multiple Sclerosis (MS) research.
Fatigue And Declines In Cognitive Functioning In Multiple Sclerosis
Krupp LB, Elkins LE
Neurology 2000 Oct 10;55(7):934-9
State Univ of New York at Stony Brook, Dept of Neurology, 11794-8121, USA
PMID# 11061247; UI# 20513425
To determine whether Cognitive Fatigue, defined as a decline in Cognitive performance over a single testing session, could be identified in MS.
Forty-five individuals with MS and 14 healthy control participants completed a 4-hour session of Cognitive testing.
That involved a baseline NeuroPsychological Battery, a continuous effortful Cognitive task (completing mental arithmetic problems administered on a computer), and a repeat NeuroPsychological Battery.
Self-report measures of Fatigue and Affect were completed before each step of the testing session.
The pattern of change in Cognitive performances over the testing session significantly differed between the MS and control participants.
Individuals with MS showed declines on measures of Verbal Memory and Conceptual Planning, whereas the control participants showed improvement.
There were no significant differences between the groups on any of the baseline Cognitive measures/P>
The MS participants performed worse than the control subjects on tests of Visual Memory, Verbal Memory, and Verbal Fluency that were repeated following the continuous effortful Cognitive task.
Both MS and control participants reported increased mental and physical Fatigue across the testing session compared with their baseline values.
Individuals with MS show declines in Cognitive performance during a single testing session and fail to show the improvement exemplified by healthy control subjects.
Evaluation Of Mitoxantrone For The Treatment Of Multiple Sclerosis
Expert Opin Investig Drugs 2000 May;9(5):1139-1149
Jain PharmaBiotech, Blasiring 7, CH-4057 Basel, Switzerland
Mitoxantrone (Novantrone((R))), an AntiNeoplastic agent, has been approved for treating patients with Secondary/Progressive Multiple Sclerosis (MS).
Mitoxantrone, which is usually categorized as an ImmunoSuppressant drug, is now also considered to be a specific ImmunoModulator.
AutoImmune mechanism of PathoGenesis of MS is the basis of ImmunoSuppressive therapeutic approaches to MS whereas ImmunoRegulatory abnormalities including defective IFN-alpha production provide the rationale for ImmunoModulating therapies.
Clinical trials have shown that Mitoxantrone had a statistically significant impact on reduction of relapse rate and delay in disability progression in these patients.
Mitoxantrone advantages as MS therapy:
- Considerable information is available about its pharmacokinetics, metabolism and toxicology from previous use in Oncology
- It requires administration only once in three months which is not only convenient for the patient but also cost-effective
- Mitoxantrone is one of the two drugs to be approved for Secondary/Progressive MS (the other is IFN-ß-1a) which offers an advantage over IFN-ß-1b preparations and Glatiramer Acetate which are indicated only for Relapsing/Remitting MS
However, the duration of therapy is usually limited to two to three years because the maximum cumulative dose recommended is 120 mg/m(2) due to concern for possible Cardiotoxicity.
Potential market value of the Mitoxantrone, based on the cost of treatment per patient and the number of patients likely to be treated in the first year of introduction, is US$210 million.
Therapeutic Developments In Multiple Sclerosis
Expert Opin Investig Drugs 2000 Apr;9(4):655-670
Univ of California, Dept of Neurology, M-794, San Francisco, CA 94143-0114, USA
Recently there have been considerable advances made in the treatment of Multiple Sclerosis.
For the first time since its initial clinical description in the 1800s, there are now available several medications which unequivocally exert favorable clinical effects, through the lowering of the biological activity of the human illness.
The therapeutic efficacy of IFN-ß preparations seems particularly well established in this regard on the basis of five large, independent, trials of this agent.
These trials have demonstrated remarkably consistent reductions in both attack rates and disability levels using a combination of clinical and Magnetic Resonance Imaging outcome measures.
The therapeutic benefit of Glatiramer Acetate also has been well established, although there is less available data on this agent than there is for Interferon.
It is important to recognize, however, that, although these agents represent an important first step in the management of patients with Multiple Sclerosis, they are only partial therapies.
In order to actually cure the illness or even to substantially improve patient outcome we need considerably better agents than we have currently.
Nevertheless, it is likely that, with improved knowledge of the role that Interferon-ß plays in the PathoGenesis of Multiple Sclerosis and with better understanding of the mechanism by which Glatiramer Acetate exerts its therapeutic effect, greatly improved therapeutic agents will be available in the future.
In addition, it seems likely that, in the future (by analogy to the experience in oncology), we will begin utilising combinations of therapies in order to better control the biological activity of this debilitating disease.
Such combination therapy will almost certainly include combinations of partially effective agents as well as combinations of these agents with other medications (e.g., the ImmunoSuppressive drugs) which, by themselves, have only been demonstrated to exert marginal clinical benefits on the course of illness.
Moreover, it also seems likely that, increasingly, therapeutic strategies that enhance or promote Myelin repair will become a major focus of clinical research in this area.
Defective T-Cell Fas Function In Patients With Multiple Sclerosis
Comi C, Leone M, Bonissoni S, DeFranco S, Bottarel F, Mezzatesta C, Chiocchetti A, Perla F, Monaco F, Dianzani U
Neurology 2000 Oct 10;55(7):921-7
Univ of Eastern Piedmont, Dept of Medical Science, Neurological Clinic, Novara, Italy
PMID# 11061245; UI# 20513423
Fas (CD95) triggers programmed cell death and is involved in shutting off the Immune Response. Inherited deleterious mutations hitting Fas or its signaling pathway cause AutoImmune LymphoProliferative Syndrome (ALPS).
To assess the possibility that decreased Fas function plays a role in development of MS.
The authors evaluated Fas function in long-term T-Cell lines (21 days of culture) from 32 patients with Relapsing/Remitting MS (RR/MS), 15 with Secondary/Progressive MS (SPMS), and 15 with Primary/Progressive MS (PP/MS) by assessing cell survival upon Fas triggering by MonoClonal AntiBodies (Mab).
Fas-induced cell death was significantly lower in all patient groups than in controls, and lower in SP/MS than in RR/MS.
Moreover, 8/15 patients with PP/MS, 10/15 with SP/MS, and 8/32 with RR/MS were frankly resistant to Fas.
Frequency of resistance to Fas-induced cell death was significantly higher in all patient groups than in controls (2/75), and higher in SP/MS than in RR/MS.
The findings that the parents of two Fas-resistant patients were Fas-resistant and that fusion of T-Cells from two Fas-resistant patients with Fas-sensitive HUT78 cells gave rise to Fas-resistant hybrid lines.
Suggest that Fas-resistance is due to inherited alterations of the Fas signaling pathway, with production of molecules exerting a dominant negative effect on a normal Fas system.
Defects of the Immune Response shutting-off system may be involved in the PathoGenesis of MS, particularly in its progressive evolution.
A Longitudinal Study Of Ventricular Volume In Early Relapsing/Remitting Multiple Sclerosis
Luks TL, Goodkin DE, Nelson SJ, Majumdar S, Bacchetti P, Portnoy D, Sloan R
Mult Scler 2000 Oct;6(5):332-7
Univ of California at San Francisco, Dept of Radiology, AC-109, 1 Irving St, San Francisco, California, CA 94143, USA
PMID# 11064443; UI# 20519927
The specific aim of this study was to determine whether progressive Brain atrophy could be detected within 18 months of establishing a diagnosis of Relapsing/Remitting Multiple Sclerosis (RRMS).
Fifteen patients with clinically definite RRMS (mean disease duration from first symptom=6 months, mean EDSS=1.2) completed 6 - 14 monthly quantitative MRI sessions.
The volume of the Lateral Ventricles was determined each month using a semi-automated thresholding technique from T1-weighted axial images.
The number of new monthly Gadolinium-enhancing (Gd+) lesions and EDSS scores were also recorded. Lateral Ventricular volumes increased significantly during this study.
When individual data were examined, statistically significant changes were observed in six of 15 patients. Monthly change in Ventricular volume was related to baseline EDSS and total number of new Gd+ lesions.
These observations indicate Brain atrophy, a putative imaging marker of diffuse DeMyelination and Axonal loss, can occur as early as 18 months after first symptons of RRMS, and is related to the baseline level of disability and to the number of new Gd+ lesions.
Multiple Sclerosis (2000) 6 332 - 337
Quality Of Life During The First 6 Months Of Interferon-ß Treatment In Patients With MS
Arnoldus JH, Killestein J, Pfennings LE, Jelles B, Uitdehaag BM, Polman CH
Mult Scler 2000 Oct;6(5):338-42
Univ Hospital 'Vrije Universiteit', Dept of Neurology, PO Box 7057, 1007 MB, Amsterdam, The Netherlands
PMID# 11064444; UI# 20519928
To determine the quality of life (QoL) of MS patients during the initial 6 months of treatment with Interferon-ß (IFN-ß).
Furthermore, to determine whether changes in QoL relate to disability, emotional state, therapeutic expectations or side effect profile.
IFN-ß has been shown to have beneficial effects on the course of MS.
Since the aim of IFN-ß treatment is not to cure but to slow down the disease it is important to know how this treatment affects QoL.
Surprisingly, the impact of treatment with IFN-ß on QoL measures has not been extensively studied so far.
Case report documentation, including EDSS, SF-36 and MADRAS scores, of 51 Relapsing/Remitting MS patients treated with IFN-ß was obtained at baseline and at months 1, 3 and 6.
Patients also filled in a form about their expectations of therapy and a questionnaire on side effects.
During treatment there was a significant linear trend indicating improvement in the Role-Physical Functioning (RPF) scale of the SF-36 (F1,50=4.9, P=0.032).
A transient decrease at month 1 was found in the scale for bodily pain, indicating more experienced pain (F1,50=19.8, P<0.001).
Subgroup analysis showed that patients with most depressive symptoms on the MADRAS at baseline contributed most to the increase in RPF scores over time (F1,24=5,6 P=0.026).
Furthermore, we found associations between adverse event scores and several domains of QoL.
Our findings suggest that IFN-ß therapy has an impact on QoL of MS patients in that it improves role-physical functioning and transiently worsens experienced bodily pain.
QoL during treatment with IFN-ß is influenced by depressive symptoms at baseline as well as by treatment-associated side-effects.
Multiple Sclerosis (2000) 6 338 - 342