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December 19, 2011
Isis Initiates Phase 1 Clinical Study of ISIS-SMNRx in Patients With Spinal Muscular Atrophy
U.S. FDA has granted both Fast Track Status and Orphan Drug Designation for ISIS-SMNRx
CARLSBAD, Calif., Dec. 19, 2011 /PRNewswire/ -- Isis Pharmaceuticals, Inc. (NASDAQ: ISIS) announced today that it has initiated a Phase 1 study of ISIS-SMNRx in patients with spinal muscular atrophy (SMA). SMA is a severe motor-neuron disease that is the leading genetic cause of infant mortality. Isis is developing ISIS-SMNRx as a potential treatment for all Types of SMA.
"SMA is a devastating disease that leads to the loss of motor neurons resulting in muscle weakness and respiratory failure in children. The genetic cause of this disease is well understood, but there are currently no effective disease-modifying therapies. Currently, treatment of SMA is entirely symptomatic and focuses on preserving muscle strength and lung function by physical therapy and assisted ventilation. This supportive approach has improved the natural history of SMA by extending life expectancy, but muscle weakness and atrophy are not affected. A disease-modifying drug like ISIS-SMNRx that specifically targets the cause of the disease could, for the first time, restore muscle strength and respiratory function and dramatically improve the children's function and quality of life," said Darryl C. De Vivo, M.D., Sidney Carter Professor of Neurology and Pediatrics and Co-Director of the Motor Neuron Center at Columbia University Medical Center............
"Our strategy to treat SMA relies on a simple, powerful antisense method that boosts SMN protein levels by fixing a genetic RNA splicing glitch. Working with Isis, we have successfully redirected splicing to increase functional SMN production. We have thoroughly validated this approach in multiple animal models, observing marked improvement in modifying the disease course in both mild and severe models of SMA," said Adrian Krainer, Ph.D., Professor of Molecular Genetics at Cold Spring Harbor Laboratory in Long Island, NY. "We look forward to translating this important discovery into an effective treatment for this serious disease."
The Phase 1 study of ISIS-SMNRx is a single-dose, dose-escalation study designed to assess the safety, tolerability and pharmacokinetic profile of the drug in children with SMA between the ages of 2-14 who are medically stable. In this study, ISIS-SMNRx will be administered intrathecally as a single injection directly into the spinal fluid. Intrathecal administration of an antisense drug, ISIS-SOD1Rx, has been shown to be safe and well tolerated in an ongoing Phase 1 study in patients with amyotrophic lateral sclerosis.
December 15, 2011
A single administration of morpholino antisense oligomer rescues spinal muscular atrophy in the mouse
A single administration of morpholino antisense oligomer rescues spinal muscular atrophy in the mouse
Abstract
Abstract
Spinal Muscular Atrophy (SMA) is an autosomal recessive disorder characterized by α-motor neuron loss in the spinal cord anterior horn. SMA results from deletion or mutation of the Survival Motor Neuron 1 gene (SMN1) and retention of SMN2. A single nucleotide difference between SMN1 andSMN2 results in exclusion of exon 7 from the majority of SMN2 transcripts, leading to decreased SMN protein levels and development of SMA. A series of splice enhancers and silencers regulate incorporation of SMN2 exon 7; these splice motifs can be blocked with antisense oligomers (ASOs) to alter SMN2 transcript splicing. We have evaluated a morpholino oligomer against ISS-N1 (HSMN2Ex7D(-10,-29)), and delivered this morpholino (MO) to postnatal day 0 (P0) SMA pups (Smn-/-, SMN2+/+, SMN∆7 +/+) by intracerebroventricular (ICV) injection. Survival was increased markedly from 15 days to over 100 days. Delayed CNS MO injection has moderate efficacy, and delayed peripheral injection has mild survival advantage, suggesting that early CNS ASO administration is essential for SMA therapy consideration. ICV treatment increased full-length SMN2 transcript as well as SMN protein in neural tissue, but only minimally in peripheral tissue. Interval analysis shows a decrease in alternative splice modification over time. We suggest that CNS increases of SMN will have a major impact on SMA, and an early increase of SMN level results in correction of motor phenotypes. Last, the early introduction by intrathecal delivery of morpholino oligomers is a potential treatment for SMA patients.
November 2011
H.R. 2149: SMA Treatment Acceleration Act of 2009
111th Congress: 2009-2010 To authorize the Secretary of Health and Human Services to conduct activities to rapidly advance treatments for spinal muscular atrophy, neuromuscular disease, and other pediatric diseases, and for other purposes.
Sponsor: Rep. Patrick Kennedy [D-RI1]
This bill never became law. This bill was proposed in a previous session of Congress. Sessions of Congress last two years, and at the end of each session all proposed bills and resolutions that haven't passed are cleared from the books. Members often reintroduce bills that did not come up for debate under a new number in the next session
S. 1158: SMA Treatment Acceleration Act of 2009
S. 1158: SMA Treatment Acceleration Act of 2009
111th Congress: 2009-2010
A bill to authorize the Secretary of Health and Human Services to conduct activities to rapidly advance treatments for spinal muscular atrophy, neuromuscular disease, and other pediatric diseases, and for other purposes.
Sponsor: Sen. Debbie Ann Stabenow [D-MI]
This bill never became law. This bill was proposed in a previous session of Congress. Sessions of Congress last two years, and at the end of each session all proposed bills and resolutions that haven't passed are cleared from the books. Members often reintroduce bills that did not come up for debate under a new number in the next session.
September 7, 2011
Mogul Using Own $100 Million in Race to Cure Daughter Prompts Novartis Aid
Mogul Using Own $100 Million in Race to Cure Daughter Prompts Novartis Aid
By Robert Langreth and Alex Nussbaum - Sep 7, 2011 12:01 AM ET
Bloomberg Markets Magazine
Goldman Sachs Group Inc. (GS) partner Dinakar Singh discovered in 2001 that his 19-month-old daughter, Arya, had a crippling genetic disease called spinal muscular atrophy.
The malady makes the nerve cells that control muscles gradually deteriorate. There are no treatments, let alone a cure, Bloomberg Markets magazine reports in its October issue. Worse still, while the gene causing the ailment had recently been discovered, nobody in the drug industry was doing much about it, he says.
“I was fearful and anxious that treatments would be developed, but far too late to save Arya,” says Singh, 42, who founded and runs New York hedge fund TPG-Axon Capital Management LP, which has $8.1 billion in assets. “We didn’t want to find out 25 years later that the science was really there but there isn’t a drug because nobody focused on it.”
June 2, 2011
Spinal Muscular Atrophy May Also Affect Sensory Neurons
Until recently, most researchers thought that problems with spinal muscular atrophy (SMA) began exclusively in motor neurons, the cells that transmit signals from the spinal cord to muscles telling them to move. But a new study, led by George Mentis, Ph.D., an investigator at Columbia University in New York City, may change that view. His results, published in Neuron,* suggest for the first time that SMA may also affect sensory neurons, the cells that transmit movements and sensations to the spinal cord.
“It changes the way we think about SMA”, said Kenneth Fischbeck, M.D., chief of the Neurogenetics Branch at the National Institute of Neurological Disorders and Stroke (NINDS) in Bethesda, Maryland.
Occurring in about 1 out of every 10,000 births, SMA is the leading inherited cause of infant death in the U.S. The most severe form of the disease begins after birth by weakening the muscles that control movements in the torso, such as breathing, and then spreads outward, weakening more distant muscles in the limbs as a child grows.
Muscle reflexes, such as the kick we make when a doctor taps our knees during a check-up, are primarily controlled by sensory and motor neurons. These neurons connect to each other in the spinal cord at sites called synapses (seen in the image above). The sensory neurons relay sensations, such as the tap, to the motor neurons. Upon receipt, the motor neurons relay the information back to the muscles, producing the kick.
March 8, 2011
Mouse Survival Motor Neuron Alleles That Mimic SMN2 Splicing and Are Inducible Rescue Embryonic Lethality Early in Development but Not Late
Spinal muscular atrophy (SMA) is caused by low survival motor neuron (SMN) levels and patients represent a clinical spectrum due primarily to varying copies of the survival motor neuron-2 (SMN2) gene. Patient and animals studies show that disease severity is abrogated as SMN levels increase. Since therapies currently being pursued target the induction of SMN, it will be important to understand the dosage, timing and cellular requirements of SMN for disease etiology and potential therapeutic intervention. This requires new mouse models that can induce SMN temporally and/or spatially. Here we describe the generation of two hypomorphicSmn alleles, SmnC-T-Neo and Smn2B-Neo. These alleles mimic SMN2 exon 7 splicing, titre Smn levels and are inducible. They were specifically designed so that up to three independent lines of mice could be generated, herein we describe two. In a homozygous state each allele results in embryonic lethality. Analysis of these mutants indicates that greater than 5% of Smn protein is required for normal development. The severe hypomorphic nature of these alleles is caused by inclusion of a loxP-flanked neomycin gene selection cassette inSmn intron 7, which can be removed with Cre recombinase. In vitro and in vivo experiments demonstrate these as inducible Smn alleles. When combined with an inducible Cre mouse, embryonic lethality caused by low Smn levels can be rescued early in gestation but not late. This provides direct genetic evidence that a therapeutic window for SMN inductive therapies may exist. Importantly, these lines fill a void for inducible Smn alleles. They also provide a base from which to generate a large repertoire of SMA models of varying disease severities when combined with other Smn alleles or SMN2-containing mice.
February 7, 2011
MOTORGRAFT™ CLINICAL TRIAL FOR SMA PLACED ON FDA CLINICAL HOLD.
MOTORGRAFT™ CLINICAL TRIAL FOR SMA PLACED ON FDA CLINICAL HOLD.
California Stem Cell’s MotorGraft™ trial for the treatment of spinal muscular atrophy (SMA) has been placed on clinical hold by the Food and Drug Administration (FDA). A clinical hold is an order that the FDA issues to a sponsor to delay a proposed trial. Clinical holds are not uncommon, especially in cases of novel treatments such as this one. Similar holds were issued by the FDA to each of the previous applications for pluripotent stem cell therapeutics, such as those submitted by NeuralStem (ALS trial), Geron Corporation (spinal cord injury trial) and Advanced Cell Technology (macular degeneration trial), and all have since been lifted and advanced to clinical trials.
CSC filed an Investigational New Drug (IND) application in November 2010 to commence a MotorGraft™ clinical trial for SMA Type I. MotorGraft™ is a high purity population of motor neuron progenitors, derived from human embryonic stem cells (hESCs), and has been shown in nonclinical studies to result in functional and histological improvement in animal models of motor neuron loss, such as SMA.
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