U P D A T E
STEM CELL THERAPIES FOR DYSMIELINATING DISEASES
The first hematopoietic stem cell transfer (HCT) for cerebral X-linked
adrenoleukodystrophy (X-ALD) was performed in 1982, with long-term results.
Leukodystrophies are a group of diseases that result form defects in
lysosomal enzymes. The lysosomes are small subcellular organelles discovered
about 60 years ago by the Belgian cytologist Christian de Duve; they contain
acidic hydrolases (pH ~4.5), enzymes by which lysosomes exert their function
in recycling molecules from cellular debris, aged organelles, bacteria,
viruses and waste compound. Deficiency of a lysosomal enzyme causes the
blockage of the corresponding metabolic pathway, leading to the accumulation
of its indigested substrates.
Approximately 40 known lysosomal storage disorders cumulatively affect 1
in 5,000 births. Signs and symptoms of the pathology are related to the
entity of substrate accumulation and sensitivity of the cell to the
abnormal storage. A general principle behind stem cell or gene therapies is
that successful engraftment will provide a source of the missing enzyme
for the life of a patient. HCT has been used for decades to cure or arrest
several neurodegenerative lysosomal storage diseases. Despite significant
progress, HCT is still associated with risks of graft failure or
graft-versus-host-disease, and there is strong interest in identifying
optimal treatment variables.
RESEARCH INTO PREVENTING EPILEPTOGENESIS
Epileptogenesis is the process by which a normal brain becomes epileptic.
Epilepsy is a disorder of brain function expressed as the periodic and
unpredictable occurrence of seizures. The term seizure denotes a fleeting
change of behavior caused by the disordered, synchronous, and rhythmic
firing of populations of neurons. It is currently unknown if antiseizure
drugs in clinical use have any prophylactic value in preventing the
development of epilepsy or epileptogenesis.
Mesial temporal lobe epilepsy (MTLE) is the most common form of partial
epilepsy. Up to two-thirds of MTLE patients exhibit a history of complicated
febrile seizures, preceding the emergence of MTLE. In many cases, as a
consequence of these febrile seizures, the hippocampus becomes sclerotic
(Ammon’s horn sclerosis), an alteration frequently associated with MTLE.
It is therefore thought that some cortical electric alterations induced by
fever lead, in the short term, to hippocampal sclerosis and, in the long
term, to MTLE. Research into mechanism by which “seizures beget seizures”
has identified some therapeutic targets that could prevent the progression
to epilepsy, including the mammalian target of rapamycin (mTOR) and the
brain-derived neurotrophic factor (BDNF)-TrkB signaling pathway. Some members
of BM&L-International Society of Neuroscience are particularly interested in
studying BDNF-TrkB pathway, which has been implicated in numerous animal
studies. TrkB activation is considered pro-epileptogenic, because mice lacking
of TrkB in forebrain neurons are unable to undergo epileptogenesis in the
kindling model of the process.
For these reasons it is thought that selective inhibitors of TrkB may be
effective anti-epileptic agents.
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