MULTIPLE SCLEROSIS and STEM CELLS
A DEVASTATING
DISEASE
Multiple
Sclerosis (MS) is a chronic and inflammatory disease based on autoimmunity[1], mainly affecting the central nervous system (CNS)
in young white adults[2]. MS is a disease which involves the damage
to the myelin sheath that is a lipoprotein-based insulation of the axons. This
sheath is essential for the electrical activity and saltatory conduction of
nerve impulses and, is an important part of the nervous system [2]. Areas of inflammation, axonal loss,
demyelination and gliosis, occurring throughout the brain and spinal cord, are the
distinctive features of MS.[3]
The disease is pathologically
characterised by the development of white matter (WM) lesions that possess
multifocal, demyelinating and inflammatory characteristics.[4] Recurrent inflammation in the CNS results in the
symptoms of MS. Oligodendrocytes are the cells that make up the myelin and, in
case of its damage or inflammation, the nerve conduction gets disrupted. This
causes the nerves to lose their function and results in the neurologic symptoms
characterising MS.[2]
Although MS has been
considered to be a condition affecting the WM, recent studies have identified
the involvement of grey matter as well.[4]
PATHOPHYSIOLOGY
The best accepted cause of the disease
postulates that the antigens of myelin are presented to appropriate T-cells by
macrophages. This activates the proliferation of T-cells. These cells cross the
blood-brain-barrier (BBB) by interacting with the intercellular adhesion
molecules and, then release cytokines that further damage myelin and sustain
the auto-immune response.[5] These subsequent events result in inflammation and the formation of
plaques in the CNS, which are observed as lesions on magnetic resonance images
(MRI).
Some forms
of systemic infection may result in up-regulated adhesion molecules on the
endothelial surface of brain and spinal cord, allowing entry of leukocytes into
the CNS. This cascade of events results in the formation of acute inflammatory,
demyelinating lesions.[6]
MS
TREATMENT
The
treatment of multiple sclerosis has changed, rather evolved, over the last 20
years. Disease-modifying therapies are an essential
requirement for MS patients. The goals of such therapy involve shortening the
duration of acute exacerbations, decrement in their frequency and provision of
symptomatic relief.[7] Such treatments are aimed at the maintenance
of function and improvement in quality of life!
The accurate
therapy for each MS sufferer, basically involves getting the right
disease-modifying therapy at the right time! This might involve the conventional
first-line or second-line medications, including Methylprednisolone for acute
relapses.
STEM
CELL THERAPY FOR MS
Autologous Hematopoietic Stem
Cell Transplantation (AHSCT) has opened new avenues for treatment of patients
suffering from MS. The emergence of multipotent Mesenchymal Stem Cells (MSCs) as
a potent cellular therapy for MS seems to be quite promising. On the basis of
triumph in treating experimental autoimmune encephalomyelitis (EAE) mouse
models, use of MSCs has progressed into clinical trials for MS. Therapy with
transplantation of stem cells is an innovative and emerging research focus to
develop new and enhanced treatments for MS. As mentioned in the press releases,
the transplantation of stem cells might be able to ‘freeze’ disease progression
in MS. With the stem cell therapy on the dawn, it is essential to acknowledge
the related details.
Hematopoietic stem cells (HSC)
are multipotent stem cells. The first report providing information about a bone
marrow transplant was published by McAllister and colleagues. The allogenic transplant
was performed in a chronic myelogenous leukaemia patient with MS. The patient
showed significant improvements in MS brain lesions.[8] Patients suffering
from active RRMS, not responding to conventional therapies and undergoing HSCT,
experience reduced disease progression, decreased relapses as well as
suppression of inflammatory MRI activity.[9]
REVIEW
The stem cell therapy
‘’reboots’’ the immune system. The action mechanism involves neuro-regeneration,
immunomodulation and neuroprotection.[10] Superficially,
the procedure involves the isolation of MSCs from adult bone marrow, followed
by ex-vivo expansion and re-infusion.
A pilot study of MSC
transplantation conducted on MS patients resulted in improved EDSS showing
stability and progression in 14.28% of participants.[10] A
Phase II randomized double-blind, placebo-controlled crossover clinical trial
has depicted lower mean cumulative number of lesions in patients receiving MSCs
as compared to those receiving placebo.[11]
Transplantation of autologous HSCs
is being offered to a small number of MS patients outside of clinical trials,
following the failure of conventional therapies and, when the further disease
progression is inevitable!
METHODOLOGY
The procedure involves
‘Mobilisation’ of stem cells from the bone marrow into the blood stream,
followed by ‘Harvesting’ of stem cells by apheresis. The harvested stem cells are expanded and ‘Cryopreserved’ for the transplantation.
Conditioning ‘Chemotherapy’, which is myeloablative or non-myeloablative,
eliminates the immune system, expectantly destructing cells involved in MS
disease activity. The isolated autologous stem cells are infused after a
certain time, leading to engraftment.
The procedure requires the
involvement of a neurologist, specialised in Multiple Sclerosis. Also, a
specialised Hematologist and AHSCT multidisciplinary team will be involved. The
criteria for this MS treatment, involves continued relapses in spite of
conventional therapies, MRI disease activity, EDSS lower than 6.0 and a short
disease course.
The side-effects involve being
susceptible to infections due to being immune-compromised, before the immunity is reassembled by the stem cells. There will be
side-effects associated with chemotherapy and, there is a possibility of
developing autoimmunity. The long-term side effects include lower fertility or
early menopause. Malignancies and small death percentages are an add-on!
Recuperation from such an
aggressive and complicated technique will, obviously, take time!
THE
PROMISE – CLINICAL TRIALS
This therapy is a germinating
research area but, so far, a finite number of small-scale clinical trials have
been conducted. The review published by Radelli and colleagues summarises the
results of 23 AHSCT clinical trials for MS.[12] The trials included
538 MS patients of which 62% had primary or secondary progressive MS. However,
the recent trials have included relapsing MS patients. The review highlighted
higher success rates of the treatment in patients with inflammatory disease activity,
lower EDSS and short disease duration. Follow-up of two years after treatment,
depicted no disease progression for 36 to 100% patients. The studies observing
progression of disease over long-term, depicted an increase in patients whose
disease progressed giving an idea of continued MS disease activity. This hints
that AHSCT might prevent continued disease progression without reversal of
subsisting damage!
Other clinical trials like
HALT-MS, involved 24 people among whom 96% had side effects. 69% showed no
progression over a period of five years. In addition, Imperial College
researchers analysed AHSCT data in 281 progressive MS patients treated between
1995 and 2006. The ones who did the best (i.e. were free
of disability progression) were young and had RRMS. There was an occurrence of
eight deaths and they were considered to be due to the treatment.
A meta-analysis conducted by
Sormani and colleagues summarised evidence on AHSCT following immune-ablative
therapy, for the management of aggressive and treatment-refractory MS. The
analysis included fifteen published studies (764 transplanted patients) between
1995 and 2016 for any form of MS. Transplant-related Mortality (TRM) was found
to be significantly higher in older studies. Higher baseline EDSS had a
significant association with high TRM. In addition, the
rate of progression was calculated to be 17.1% and 23.3% at two and five years,
respectively. With reference to no evidence of disease activity (NEDA), at two
years the pooled proportion was found to be 83% and, 67% at 5 years.[13]
Therefore, the
surfacing evidence on this therapy for MS signifies a large benefit/risk
profile. Early results do come with encouragement as well as noteworthy
improvements! However, there is an essential requirement of longer term
clinical trials to assess the efficacy and safety of stem cell therapies.
