Weinstock L, Furness AM, Herron S, Smith SS, Sankar S, DeRosa
SG, Gao D, Mepyans ME, Scotto Rosato A, Medina DL, Vardi A, Ferreira
NS, Cho SM, Futerman AH, Slaugenhaupt SA, Wood LB, Grishchuk Y. Fingolimod
Phosphate Inhibits Astrocyte Inflammatory Activity in Mucolipidosis IV. Hum Mol
Genet. 2018 May 16. doi: 10.1093/hmg/ddy182. [Epub ahead of print]
Abstract
Mucolipidosis IV (MLIV) is an orphan neurodevelopmental
disease that causes severe neurologic dysfunction and loss of vision. Currently
there is no therapy for MLIV. It is caused by loss of function of the lysosomal
channel mucolipin-1, also known as TRPML1. Knockout of the Mcoln1 gene in a
mouse model mirrors clinical and neuropathological signs in humans. Using this
model, we previously observed robust activation of microglia and astrocytes in
early symptomatic stages of disease. Here we investigate the consequence of
mucolipin-1 loss on astrocyte inflammatory activation in vivo and in vitro and
apply a pharmacological approach to restore Mcoln1-/- astrocyte homeostasis
using a clinically approved immunomodulator, fingolimod. We found that
Mcoln1-/- mice over-express numerous pro-inflammatory cytokines, some of which
were also over-expressed in astrocyte cultures. Changes in the cytokine profile
in Mcoln1-/- astrocytes are concomitant with changes in phospho-protein
signaling, including activation of PI3K/Akt and MAPK pathways. Fingolimod
promotes cytokine homeostasis, down-regulates signaling within the PI3K/Akt and
MAPK pathways, and restores the lysosomal compartment in Mcoln1-/- astrocytes.
These data suggest that fingolimod is a promising candidate for preclinical
evaluation in our MLIV mouse model, which, in case of success, can be rapidly
translated into clinical trial.
___________________________________________________________________
In the nearly five decades since Mucolipidosis Type IV, or
ML4, was first identified, children with the disease have had little promise of
ever having a “normal” life.
ML4 generally strikes their nervous system early and hard.
Most never learn to walk or talk and have a maximum mental capacity of about 18
months. By their teen years, the disease steals their eyesight, and by their
20s, their life is at stake.
But just in the past few months, research using an already
FDA-approved drug is giving parents like Randy and Caroline Gold of Atlanta
hope.
In the nearly five decades since Mucolipidosis Type IV, or
ML4, was first identified, children with the disease have had little promise of
ever having a “normal” life.
ML4 generally strikes their nervous system early and hard.
Most never learn to walk or talk and have a maximum mental capacity of about 18
months. By their teen years, the disease steals their eyesight, and by their
20s, their life is at stake.
But just in the past few months, research using an already
FDA-approved drug is giving parents like Randy and Caroline Gold of Atlanta
hope.
“I think that this drug is the first of many treatments that
will be available to kids with ML4,” Randy Gold said. “We are incredibly
excited because it is the first opportunity to treat a kid affected by ML4.”
Gold is president of the Mucolipidosis Type IV Foundation,
an international nonprofit focused on funding research directed at
understanding the genetic disease and developing treatments.
The Golds’ 10-year-old daughter, Eden, was diagnosed with
ML4 in 2009. The couple haven’t been shy about soliciting donations for the
foundation to help fund research or talking about their experiences caring for
Eden.
They’ve been on the front lines since 2010 doing what they
could to not only improve Eden’s life but the lives of all kids with ML4. They
first shared their story here last summer…
As this year’s ML4 International Research Conference
approached late last month, Randy Gold reached out again, excited about the
promise of this new research.
He knows the drug is not going to instantly turn Eden into a
“typical” kid; that she is not going to wake up tomorrow and get herself
dressed for school.
And yet, it’s hard not to be excited about this first
treatment.
“We’re certain more treatments will have to follow,” Gold
said. “Unfortunately, this drug is not one and done.”…
With funding from the foundation, researchers began testing
the drug a year ago in mice cells, then expanded to do more advanced testing to
validate their findings. The results were published in the May issue of The
Journal of Human Molecular Genetics.
Further testing is now being done in a bigger study of live
mice, with study results expected late this year.
“This is the first time with this disease that we have a
drug that shows a level of rescue, taking a cell and returning it to a
healthier state,” Oberman said. “If the results from the mouse study are as
positive as we hope, it could mean a clinical trial in kids with ML4 in 2019,
giving us the first opportunity to treat these kids with something that the FDA
agrees will have a positive impact on them. It’s not a cure, but it will treat
a major symptom of this disease, neurological inflammation. I can’t tell you
now what it will look like in each individual child, but we know this is
treating something that is a significant part of this disease.”
https://www.ajc.com/lifestyles/health/fda-approved-drug-holds-first-promise-for-kids-with-genetic-disease/qgEo9Mtq3oaW5uHKSOkb4N/?icmp=np_inform_variation-control
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