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New research carried out at NIH’s National Institute of Neurological
Disorders and Stroke (NINDS) has yielded promising results in the
treatment options for SMA.The study is published in The Journal of
Clinical Investigation Advance Online Publication, February 22, 2007.
Previous studies have shown that HDAC inhibitors can increase the amount of SMN2 expression in cultured cells and that treating pregnant mice with an HDAC inhibitor can increase the survival of their babies with SMA. Preliminary clinical trials are now underway to test several HDAC inhibitors in children who have SMA. However, the drugs in those clinical trials are weak HDAC inhibitors with other biological effects that may limit their usefulness for treating this disease. None of the previous studies has demonstrated that HDAC inhibitors can extend survival when delivered after symptoms appeared.
Charlotte J. Sumner, M.D., & her colleagues at NINDS tested trichostatin A (TSA), a histone deacetylase inhibitor(HDAC) in cells from SMA patients and in a mouse model of SMA. They found that the drug increased the amount of SMN2 gene activity in both the cultured cells and the mouse model. Daily injections of TSA to the SMA mice, starting when the mice were 5 days old when they had started showing clear symptoms of disease being significantly underweight and with markedly impaired righting reflex. The treated mice lived 19 percent longer, on average, than mice that did not receive TSA. About three-fourths of the treated mice showed improved survival compared to control mice with the remaining showing no improvement. The treated mice had less weight loss and better righting reflexes, walking ability, and forelimb grip strength than mice that did not receive TSA. Examination showed that the TSA-treated mice also had larger neurons in the spinal cord, thicker muscle fibers, and more muscle mass than untreated mice.
Currently there are no studies that have proven the effectiveness of HDAC inhibitors in humans.
Spinal muscular atrophy (SMA) is a severe and often devastating neurologic disorder of infants and children. The clinical spectrum extends from the most severely affected (SMA I) to those who have relatively preserved strength and a normal life expectancy (SMA III). There is no known treatment for this disorder, but recent findings have led to biologically plausible candidates for therapeutic intervention. Clinical trials for this disease are being planned and executed. We sought to address the challenges of and opportunities for effectively organizing trials of potential new therapeutic agents.
INCIDENCE AND PREVALENCE.
Although rare, SMA is the most common fatal neuromuscular disease of infancy and the third most common diagnosis of neuromuscular diseases seen in clinics for children <18 years.One in 50 people carries this autosomal recessive gene. SMA I has the highest incidence of the three types, but because these children usually do not survive past age 2 years, SMA II and III are more prevalent than SMA I.5 Estimates based on a national voluntary registry and a few prospective studies give a frequency of 8 to 11 per 100,000 live births. There have been no epidemiology studies in North America.
SMA TYPE I.
SMA type I is called  Werdnig-Hoffmann disease or infantile onset SMA. Weakness and profound hypotonia are noticeable in the first few months of life. There is a striking discrepancy between the infant's normal social awareness and interaction and motor development. Spontaneous movements are very limited except in the hands and feet, and the infant lies on his or her back in a frog-leg position. Deep tendon reflexes are absent but sphincter tone and sensation are intact. Poly-minimyoclonus, or muscle trembling, can be seen in the fingers, and fasciculations are often present in the tongue. Because intercostal muscles are weak, the diaphragm is used to breathe and pectus excavatum and flaring of the lower ribs result. The babies tire easily when feeding and may lose weight and fail to thrive. Both weaknesses from malnutrition and respiratory insufficiency cause susceptibility to aspiration. The most common cause of death is respiratory failure; children rarely survive beyond age 2 years.
SMA TYPE II.
In type 2 disease, intermediate or juvenile SMA, milestones are usually normal until onset of weakness between 6 and 18 months of age. The legs tend to be weaker than the arms, so children often come to medical attention because of failure to walk. The pattern of deep tendon reflexes may be variable. Children can sit without support when placed, sometimes walk with bracing, and are now surviving into adolescence and beyond. Good pulmonary function and care seems to be a key to prolonged survival.
SMA TYPE III.
In patients with the mildest form, type 3 (Kugelberg-Welander disease), independent ambulation is achieved and survival is usually normal. Onset of apparent weakness may be anytime after age 18 months, but is often in late childhood or adolescence. It may be confused with limb-girdle muscular dystrophy. The gait is typically waddling with lumbar lordosis, genu recurvatum, and a protuberant abdomen. Deep tendon reflexes may be present or absent. If onset of weakness is later than age 2 years, it is highly likely that ambulation will be possible into the fifth decade or beyond.Although the clinical picture may not be typical of a neurodegenerative disease, a decrease in motor units over time has been documented.The classification for SMA into three types is useful for understanding prognosis but they are biologically not distinct. With fewer copies of survival motor neuron gene (SMN) 2 (or SMN copy count), there is increase in severity of weakness. However, all patients must have at least one copy of the SMN2 gene, because complete loss of SMN would be an embryonic lethal condition.
GENETICS OF SMA
SMA is an autosomal recessive disorder caused by homozygous deletions or mutations of the SMN1 gene at the 5 q11 locus which result in reduction of full length (fl-SMN) protein necessary for lower motor neuron function.
There are two copies of the SMN gene on chromosome 5q that code for SMN protein: SMN1 and SMN2.
SMN1 encodes fl-SMN protein, while SMN2 mostly encodes a protein that is lacking in exon 7 (Δ7-SMN, a less stable protein).
The severity of the disease can be modified by extra copies of the SMN2 gene.17 All patients have reduced levels of fl-SMN protein, but those with the phenotype of SMA type 1 have as little as 9% of the normal amount of fl-SMN, those with SMA type 2 have 14%, and with SMA type 3, about 18%. Once fl-protein levels approach 23% of normal levels, motor neuron function appears normal, and carriers usually have 45 to 55% fl-SMN protein.
POTENTIAL FOR THERAPIES.
one strategy for pharmacologic intervention in SMA is to enhance production of fl-SMN. Mechanisms for potential specific therapies include enhanced expression of the SMN2 gene, altering SMN2 transcript splicing to increase the level of fl-SMN RNA, and other strategies to increase the level or activity of SMN. Active agents including histone deacetylase (HDAC) inhibitors have been identified that can increase the level of fl-SMN. These compounds cause deacetylation of histone as well as nonhistone proteins and transcription factors, and thereby can upregulate SMN mRNA ratios.24 HDAC inhibitors used in humans for other clinical conditions are phenylbutyrate and hydroxyurea.
EXISTING RESOURCES AND CURRENT THERAPEUTIC TRIALS.
There are projects funded by the National Institute of Neurologic Disorders and Stroke (NINDS) and by private foundations working on generating candidate therapies for SMA. The NINDS SMA Project is a preclinical pilot program to develop therapeutics for SMA, using guidance from industry, academia, and the FDA ( http://www.smaproject.org ). Candidate compounds will be identified and will undergo extensive screening to see if they enhance fl-SMN expression, have pharmaceutical suitability, and are active in animal models of SMA. This program supports facilities to chemically optimize active compounds, to perform a standardized battery of cellular assays, and to test drugs in animal models of SMA. In addition, private foundations aggressively support therapeutics development efforts that generate candidates for clinical testing. These organizations fund additional resources for clinical research in SMA such as the Indiana University School of Medicine International SMA Patient Registry, funded by Families of SMA since 1986. The registry has compiled information on over 1,100 families including type of SMA, tests used for diagnosis, age at diagnosis, living status, and cause of death. The registry is a source of statistical data and serves as a database of patients for clinical trials ( http://www.fsma.org/registry2002.shtmal ).
Currently in the United States, there are three collaborative clinical trial groups focused on SMA. AmSMART (American Spinal Muscular Atrophy Randomized Trials, http://acsresearch.swmed.edu/amsmart/) is a clinical consortium that has established a framework for clinical trials, has investigated and validated outcome measures, has performed a pilot trial of treatment with creatine, and plans future pilot trials with other drugs. Project Cure SMA ( http://www.fsma.org/clinicaltrials/shtml ) has also established a clinical network to do natural history studies, refine clinical outcome measures, and collect data on safety and tolerability of valproate and other drugs. The third network, the Pediatric Neuromuscular Clinical Research Network, has recently been established to provide a regional network in the Northeast for conducting natural history studies and finding and testing effective treatments for SMA ( http://www.unmc.edu/sma/ ). In addition, there are active clinical trials consortia in Europe as well (European Neuromuscular Center, http://www.enmc.org/trials/trial.cfm ).
More information from NINDS on SMA can be found here http://www.ninds.nih.gov/disorders/sma/sma.htm
Avila AA, Burnett BG, Taye AA, Gabanella F, Knight MA, Hartenstein P, Cizman Z, Di Prospero NA, Pellizzoni L, Fischbeck KH, Sumner CJ. "Trichostatin A increases SMN expression and survival in a mouse model of spinal muscular atrophy." The Journal of Clinical Investigation, Advance Online Publication, February 22, 2007, doi: 10.1172/JCI29562.
The National Institutes of Health (NIH) - The Nation's Medical Research
Agency - includes 27 Institutes and Centers and is a component of the
U. S. Department of Health and Human Services. It is the primary
Federal agency for conducting and supporting basic, clinical, and
translational medical research, and it investigates the causes,
treatments, and cures for both common and rare diseases. For more
information about NIH and its programs, visit www.nih.gov.
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