{"606495":{"#nid":"606495","#data":{"type":"news","title":"In Child-Crippling Mucolipidosis IV, Drug Shows Hope in Lab Cultures","body":[{"value":"\u003Cp\u003EMucolipidosis IV debilitates afflicted children\u0026rsquo;s nervous systems in their first year of life, steals their eyesight in their teens and often takes their lives in their twenties, and so far, there is no therapy to fight it. Now, lab tests using an existing prescription drug have shown initial hope for a future treatment.\u003C\/p\u003E\r\n\r\n\u003Cp\u003EFingolimod is used to treat a form of multiple sclerosis and is already FDA-approved. Researchers at the Georgia Institute of Technology, and at the Massachusetts General Hospital Research Institute have led successful testing of fingolimod, \u003Cem\u003Ein vitro\u003C\/em\u003E, i.e. on lab cultures, in cells originating from the brains of mice genetically augmented to mimic mucolipidosis IV (MLIV).\u003C\/p\u003E\r\n\r\n\u003Cp\u003EThe next step will be tests in living mice, and researchers are hopeful that continued research progress may lead to a quicker than usual approval for human clinical drug trials. Fingolimod has not been tested on human MLIV cells and is not yet prescribed to treat MLIV.\u003C\/p\u003E\r\n\r\n\u003Cp\u003EThe researchers published their \u003Ca href=\u0022https:\/\/academic.oup.com\/hmg\/advance-article\/doi\/10.1093\/hmg\/ddy182\/4996739\u0022 target=\u0022_blank\u0022\u003Estudy in the latest edition of the journal \u003Cem\u003EHuman Molecular Genetics\u003C\/em\u003E\u003C\/a\u003E. Their work was funded by the \u003Ca href=\u0022http:\/\/ml4.org\/\u0022 target=\u0022_blank\u0022\u003EML4 Foundation\u003C\/a\u003E.\u003C\/p\u003E\r\n\r\n\u003Ch4\u003E\u003Cstrong\u003ECellular junk accumulation\u003C\/strong\u003E\u003C\/h4\u003E\r\n\r\n\u003Cp\u003EMucolipidosis IV is a rare hereditary disease with a cruelty that can rival cerebral palsy\u0026rsquo;s. MLIV strikes very early in life and goes from bad to worse.\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u0026ldquo;Around the age of 9 months, you see cognitive deficits,\u0026rdquo; said \u003Ca href=\u0022http:\/\/www.me.gatech.edu\/faculty\/wood\u0022 target=\u0022_blank\u0022\u003ELevi Wood, an assistant professor in Georgia Tech\u0026rsquo;s School of Mechanical Engineering\u003C\/a\u003E. Wood\u0026rsquo;s research focuses on neurological diseases. \u0026ldquo;The children never learn to speak, and hardly at all to walk.\u0026rdquo;\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u0026ldquo;When they go blind, it changes everything so badly, because the children stop recognizing faces, including their parents\u0026rsquo;,\u0026rdquo; said \u003Ca href=\u0022https:\/\/cgm.massgeneral.org\/faculty\/yulia-grishchuk\/\u0022 target=\u0022_blank\u0022\u003EYulia Grishchuk, a junior faculty member at Mass General\u003C\/a\u003E and Harvard Medical School. She co-led the study with Wood.\u003C\/p\u003E\r\n\r\n\u003Cp\u003EMLIV is caused by a single mutated gene.\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u0026ldquo;It disrupts the lysosome (a cell organelle), which is responsible for recycling waste, and this causes it to pile up in the cell,\u0026rdquo; Grishchuk said. \u0026ldquo;Junk accumulates in all the cells of the body, but the brain suffers the most, and the eyes.\u0026rdquo;\u003C\/p\u003E\r\n\r\n\u003Ch4\u003E\u003Cstrong\u003ELab success: Astrocyte observation\u003C\/strong\u003E\u003C\/h4\u003E\r\n\r\n\u003Cp\u003EThe disease particularly throws off a group of cells in the brain called glial cells. One type, oligodendrocytes, produces the white sheathing called myelin that protects many neurons.\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u0026ldquo;These patients, and also our lab mice, have ineffective myelination,\u0026rdquo; Wood said. \u0026ldquo;That\u0026rsquo;s one thing that may be impeding brain function.\u0026rdquo;\u003C\/p\u003E\r\n\r\n\u003Cp\u003EOther glial cells, microglia\u0026nbsp;and astrocytes, both have immune functions in the brain, and in this study, the researchers were able to observe for the first time that the latter were not behaving normally.\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u0026ldquo;The astrocytes\u0026rsquo; activity is unusual in this disease and associated with increased inflammation,\u0026rdquo; Grishchuk said.\u003C\/p\u003E\r\n\r\n\u003Cp\u003EGrishchuk trained in the lab of \u003Ca href=\u0022https:\/\/cgm.massgeneral.org\/faculty\/susan-a-slaugenhaupt\/\u0022\u003ESusan Slaugenhaupt\u003C\/a\u003E, an MLIV pioneer who initially discovered the causal gene at Mass General and developed the mouse model used to study and fight the disease. Slaugenhaupt collaborated on this study.\u003C\/p\u003E\r\n\r\n\u003Ch4\u003E\u003Cstrong\u003ELab success: Astrocyte regulation\u003C\/strong\u003E\u003C\/h4\u003E\r\n\r\n\u003Cp\u003EA certain type of multiple sclerosis, remitting-relapsing MS (RRMS), shares this odd astrocyte behavior, which gave the researchers the idea of testing a drug used to treat that disease in MLIV cell samples.\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u0026ldquo;We thought fingolimod would have a good chance because it works on astrocytes in MS,\u0026rdquo; Wood said.\u003C\/p\u003E\r\n\r\n\u003Cp\u003EIt tested successfully in the researchers\u0026rsquo; mouse-MLIV-astrocyte lab cultures, inhibiting the astrocytes\u0026rsquo; abnormal behavior. Now, the researchers want to move on to live mouse models to see if treatment helps brain function.\u003C\/p\u003E\r\n\r\n\u003Cp\u003EFingolimod was recently improved for pediatric treatment of RRMS. Also, if it positively affects astrocytes in clinical trials, there is hope fingolimod could also improve other glial cells\u0026rsquo; functioning.\u003C\/p\u003E\r\n\r\n\u003Ch4\u003E\u003Cstrong\u003EMLIV\u0026rsquo;s particular challenges\u003C\/strong\u003E\u003C\/h4\u003E\r\n\r\n\u003Cp\u003EVery few people carry the mutated gene that causes MLIV, and the gene is recessive, meaning that to get the disease, not only do both parents have to carry it, but both have to pass on their respective recessive gene to the child.\u003C\/p\u003E\r\n\r\n\u003Cp\u003ESince the affliction is so rare, parents of a child with MLIV usually spend years going through misdiagnoses before correctly determining their child\u0026rsquo;s disease. And, ironically, though the effects of the disease are obviously visible, early on, neural damage is not.\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u0026ldquo;It\u0026rsquo;s neurodevelopmental in very early childhood. The neurodegeneration kicks in much later in life,\u0026rdquo; Grishchuk said.\u003C\/p\u003E\r\n\r\n\u003Cp\u003EOnce a clinician or parent stumbles onto the disorder in medical literature, it can be confirmed by a genetic test. But then the parents are confronted with the cruel fact that there is no treatment at all for MLIV.\u003C\/p\u003E\r\n\r\n\u003Ch4\u003E\u003Cstrong\u003EResearch fight against MLIV\u003C\/strong\u003E\u003C\/h4\u003E\r\n\r\n\u003Cp\u003EAs with many rare diseases, research and development funding for MLIV is scarce, so researchers are pushed to find promise in existing FDA-approved medications for other conditions, so that clinical trials may become more likely.\u003C\/p\u003E\r\n\r\n\u003Cp\u003EIf fingolimod does make it to a clinical trial to treat MLIV, it may be a one-shot proposition. If the trial fails, then subsequent clinical trials may not be possible for many years, since the patient pool is very small and participation in a failed clinical trial often rules out a patient\u0026rsquo;s inclusion in further trials with different medications.\u003C\/p\u003E\r\n\r\n\u003Cp\u003EIf the drug advances to become an available treatment, it would ideally be combined with early disease detection, so that therapy could begin as young as possible, thus preempting neurological ravages and rescuing brain function without delay.\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u003Cstrong\u003E\u003Cem\u003ELike this article?\u0026nbsp;\u003Ca href=\u0022http:\/\/www.rh.gatech.edu\/subscribe\u0022 target=\u0022_blank\u0022\u003EGet our email newsletter here.\u003C\/a\u003E\u003C\/em\u003E\u003C\/strong\u003E\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u003Cem\u003EThese authors collaborated in the study: Laura Weinstock and Sitara Sankar of Georgia Tech; Amanda Furness, Shawn Herron, Sierra Smith, Samantha DeRosa, Dadi Gao and Molly Mepyans of Massachusetts General, Anna Scotto Rosato and Diego Medina of Italy\u0026rsquo;s Telethon Institute of Genetics and Medicine; Ayelet Vardi, Soo Min Cho and Anthony Futerman of Israel\u0026rsquo;s Weizmann Institute of Science; and Natalia S. Ferreira of Switzerland\u0026rsquo;s University of Zurich-Vetsuisse. Findings and opinions in the paper are those of the authors and not necessarily of the funding agency.\u003C\/em\u003E\u003C\/p\u003E\r\n","summary":null,"format":"limited_html"}],"field_subtitle":"","field_summary":[{"value":"\u003Cp\u003EMedicine offers no treatment for children crippled by mucolipidosis IV, which hits them in the first year of life and gradually becomes fatal. But researchers battling it with limited means at their disposal have captured a glimmer of hope in lab tests on an existing drug.\u003C\/p\u003E\r\n","format":"limited_html"}],"field_summary_sentence":[{"value":"Tests show initial hopes in the fight against Mucolipidosis IV, a rare but extremely crippling disease that strikes in infancy."}],"uid":"31759","created_gmt":"2018-05-25 16:34:52","changed_gmt":"2018-06-01 13:28:09","author":"Ben Brumfield","boilerplate_text":"","field_publication":"","field_article_url":"","dateline":{"date":"2018-05-29T00:00:00-04:00","iso_date":"2018-05-29T00:00:00-04:00","tz":"America\/New_York"},"extras":[],"hg_media":{"606491":{"id":"606491","type":"image","title":"Mucolipidosis IV sufferer Daniella","body":null,"created":"1527260970","gmt_created":"2018-05-25 15:09:30","changed":"1527859654","gmt_changed":"2018-06-01 13:27:34","alt":"","file":{"fid":"231322","name":"Danilla 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