A study led by Brian McCabe and his team from the Motor Neuron Center at Columbia University Medical Center (CUMC) suggests that contrary to existing theories, Spinal muscular atrophy (SMA), results primarily from motor circuit dysfunction and not motor neuron or muscle cell dysfunction

 SMA, a hereditary neuromuscular disease characterized by muscle atrophy and weakness is caused by defects in a gene called SMN1 (survival motor neuron 1), which encodes the SMN protein.

There are several forms of SMA, distinguished by time of onset and clinical severity. The most severe form, Type 1, appears before six months of age and generally results in death by age two. In milder forms, symptoms may not appear until much later in childhood or even in early adulthood. There is no treatment for SMA, which is estimated to affect as many as 10,000 to 25,000 children and adults in the United States and is the leading genetic cause of death in infants.

The researchers studied¹ Drosophila (Fruit Flies) SMN mutants which had been genetically altered so that every cell had a defective copy of the SMN1 gene. The mutant flies had reduced muscle size and defective locomotion, motor rhythm, and motor neuron neurotransmission. When fully functional copies of SMN1 were introduced into the flies' motor neurons or muscle cells, the cell types previously thought to be affected, the flies unexpectedly did not show any improvement.

However when SMN1 was returned to other motor circuit neurons - in particular, proprioceptive neurons and interneurons – the muscle size and motor function were restored. The proprioceptive neurons in motor circuits pick up and relay information to the spinal cord and brain about the body's position in space, which is then processed in the CNS and relayed via interneurons back to the motor neurons to stimulate muscle movement.

In another experiment the researchers demonstrated that in fruit flies with defective SMN1, proprioceptive neurons and interneurons do not produce enough neurotransmitters. The muscle size and motor function improved when the flies' potassium channels were genetically blocked thereby increasing neurotransmitter output. The same effect was seen when the flies were given drugs that block potassium channels, leading to suggestions that this class of drugs might help patients with SMA.

Supported by these findings, in July 2012, the SMA Clinical Research Center at CUMC launched a clinical trial of a potassium channel blocker called dalfampridine (Ampyra) for the treatment of patients with SMA.

The study will assess whether the Dalfampriine improves walking ability and endurance in adults with SMA Type 3, compared with placebo. Claudia A. Chiriboga, MD, MPH, associate professor of Clinical Neurology at CUMC, is the lead clinical investigator. Ampyra was approved by the FDA for the treatment of patients with multiple sclerosis in 2010.

In a second study², led jointly by Livio Pellizzoni, PhD, assistant professor of Pathology and Cell Biology in the Motor Neuron Center, and Dr. McCabe looked at why even though mutations in the disease gene SMN1 results in reduced expression in all cells, its only the motor system that is affected in patients with SMA.

Working with models of SMA in mammalian cells, fruit flies, zebrafish, and mice, the researchers demonstrated that SMN1 deficiency disrupts a fundamental cellular process known as RNA splicing (removal of parts of RNA called introns so that a gene can be translated into protein) with detrimental effects on the expression of a subset of genes that contain a rare type of intron.

By studying the function of this group of genes affected by the loss of SMN1, the researchers discovered a novel gene - which they named stasimon - that is critically required for motor circuit activity in vivo. They further showed that restoring expression of stasimon was alone sufficient to correct key aspects of motor dysfunction in both invertebrate and vertebrate models of SMA.

The implication is that this gene and the pathway in which it functions might be new candidate therapeutic targets The loss of the SMN1 gene has been directly linked to defective splicing of a critical neuronal gene to motor circuit dysfunction. The study thus points to SMA being a disease of RNA splicing. 

References:

1. SMN Is Required for Sensory-Motor Circuit Function in Drosophila. Wendy L. Imlach, Erin S. Beck, Ben Jiwon Choi, Francesco Lotti, Livio Pellizzoni, Brian D. McCabe. Cell - 12 October 2012 (Vol. 151, Issue 2, pp. 427-439)

2. An SMN-Dependent U12 Splicing Event Essential for Motor Circuit Function. Francesco Lotti, Wendy L. Imlach, Luciano Saieva, Erin S. Beck, Le T. Hao, Darrick K. Li, Wei Jiao, George Z. Mentis, Christine E. Beattie, Brian D. McCabe, Livio Pellizzoni. Cell - 12 October 2012 (Vol. 151, Issue 2, pp. 440-454)

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Published: 15 October 2012

Last Updated: 08 February 2020

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A Phase I clinical trial led by investigators from the University of California, San Francisco (UCSF) has shown that neural stem cells successfully engrafted into the brains of patients and appear to have produced myelin. The findings have been published in the Oct 10, 2012 issue of Science Translational Medicine.

Once transplanted and engrafted, neural stem cells have the potential to differentiate into a number of different brain cell types, depending on the area of the brain into which they are inserted. The sites chosen for the Phase I study were known from animal studies to be the most likely to result in the formation of oligodendrocytes.

In the trial, allogeneic human neural stem cells (HuCNS-SCs) developed by Stem Cells, Inc., of Newark, California, were injected directly into the frontal lobe white matter of four young children with an early-onset, fatal form of a condition known as Pelizaeus-Merzbacher disease (PMD).

Immunosuppression was administered for 9 months. During 2010-2011, the children with PMD, who were included in the trial, underwent serial neurological evaluations, developmental assessments, and cranial magnetic resonance imaging (MRI) and MR spectroscopy, including high-angular resolution diffusion tensor imaging (DTI). The investigators found evidence that the stem cells had successfully engrafted, receiving blood and nutrients from the surrounding tissue and integrating into the brain.

The Phase 1 trials designed to test safety and preliminary efficacy demonstrated that the neural stem cells were safe in the patients’ brains one year post transplant. No clinical or radiological adverse effects were directly attributed to the donor cells. Reduced T1 and T2 relaxation times were observed in the regions of transplantation 9 months after the procedure in the three subjects. Normalized DTI showed increasing fractional anisotropy and reduced radial diffusivity, consistent with myelination, in the region of transplantation compared to control white matter regions remote to the transplant sites. The MRI findings suggested myelination in the regions that have been transplanted providing indirect evidence that the stem cells had become oligodendrocytes and were producing myelin.

These results have thus provided for the first time evidence that transplanted neural stem cells are able to produce new myelin in patients with a severe myelination disease. The MRI findings from the clinical trial are further supported by findings from a separate study² by in a separate study by researchers at Oregon Health & Science University's Papé Family Pediatric Research Institute which showed that neural stem cells injected into mouse models became oligodendrocytes and formed myelin.

 

The PMD clinical trial researchers included Principal investigator David H. Rowitch, MD, PhD, a professor of pediatrics and neurological surgery at UCSF, chief of neonatology at UCSF Benioff Children's Hospital and a Howard Hughes Medical Institute Investigator and co-principal investigator Nalin Gupta, MD, PhD, associate professor of neurological surgery and pediatrics and chief of pediatric neurological surgery at UCSF Benioff Children's Hospital.

 

 

The study, one of the first neural stem cell trials ever conducted in the United States, is symbolical of UCSF’s pioneering role in the stem cell field.

In 1981, Gail Martin, PhD, professor of anatomy, co-discovered embryonic stem cells in mice.

 

In 2001, Roger Pedersen, PhD, professor emeritus of obstetrics, gynaecology and reproductive sciences, derived two of the first human embryonic stem cell lines.

 

In 2012, Shinya Yamanaka, MD, PhD, of the UCSF-affiliated Gladstone Institutes and Kyoto University, received the Nobel Prize in Physiology or Medicine for his discovery that adult cells can be reprogrammed to behave like embryonic stem cells

 

Citations

¹Gupta N, Henry RG, Strober J, Kang SM, Lim DA, Bucci M et al. (2012) Neural stem cell engraftment and myelination in the human brain. Sci Transl Med 4 (155):155ra137. DOI: 10.1126/scitranslmed.3004373 PMID: 23052294.

²Uchida N, Chen K, Dohse M, Hansen KD, Dean J, Buser JR et al. (2012) Human neural stem cells induce functional myelination in mice with severe dysmyelination. Sci Transl Med 4 (155):155ra136. DOI: 10.1126/scitranslmed.3004371 PMID: 23052293.

 About Pelizaeus-Merzbacher disease (PMD)

• Rare congenital X-linked recessive leukodystrophy
• Incidence of 1:200,000 to 1:500,000
• Caused by mutation of myelin protein proteolipid protein 1 (PLP1), resulting in hypomyelination 
• Leading to death between ages 10 and 15
• Oligodendrocytes are unable to myelinate axons, resulting in loss of normal axonal conduction and neurological dysfunction in the short term, eventually leading to axonopathy and neurodegeneration.
• PMD is one of a spectrum of diseases associated with PLP1, which also includes Spastic Paraplegia Type 2 (SPG2)
• Four types recognised
  • Congenital PMD -early-onset severe form of PMD presents with profound neurodevelopmental deficits.
  • Classic PMD, in which the early symptoms include muscle weakness, involuntary movements of the eyes (nystagmus), and delays in motor development within the first year of life;
  • Complicated SPG2, which features motor development issues and brain involvement, and,
  • Pure SPG2, which includes cases of PMD that do not have neurologic complications.

Further Reading

Pelizaeus-Merzbacher disease (PMD)

 

 

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Published: 13 October 2012

Last Updated: 08 February 2020

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The ICNA is happy to announce an educational program to be held in Pune, India on January 19-20, 2013 in collaboration with Pune Neurological Society.

The ICNA will be represented by Doctors Harry Chugani, Banu Anlar, Linda De Meirleir, Peter Camfield, Carol Camfield.

The local organizer is Dr Nandan Yardi, K.E.M. Hospital Research Centre, Pune

 

 

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Published: 07 October 2012

Last Updated: 08 February 2020

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The 48-week results from the ongoing Phase IIb clinical trial of eteplirsen for the treatment of Duchenne muscular dystrophy (DMD)has been announced. Eteplirsen is an exon-skipping compound that addresses one of the underlying genetic defects in Duchenne muscular dystrophy.

At 48 weeks eteplirsen demonstrated a significant and unprecedented clinical benefit on the primary clinical outcome measure, the 6-minute walk test, and met the primary efficacy endpoint of the study, an increase in novel dystrophin. The results represent the potential medical breakthrough that eteplirsen represents for the treatment of DMD.

Although only about 13% of boys with Duchenne muscular dystrophy have the specific mutation targeted by eteplirsen, the implications for all Duchenne muscular dystrophy patients with related genetic mutations are clearly evident.

Clusters of proteins are spaced at intervals along the membrane of each muscle fiber. The presence of dystrophin, or the related protein utrophin, appears to be necessary for the other proteins in the cluster to assemble at the membrane. Courtesy: Muscular Dystrophy Association

Trial Results

Eteplirsen administered once weekly at either 30mg/kg or 50mg/kg for 48 weeks (n=8) resulted in a statistically significant increase in dystrophin-positive fibers of 47.0% of normal.

The placebo/delayed treatment cohort, which received 24 weeks of eteplirsen at either 30mg/kg or 50mg/kg following 24 weeks of placebo (n=4), produced a statistically significant increase in dystrophin-positive fibers of 38.3% of normal.

In addition, eteplirsen administered once weekly at 50mg/kg over 48 weeks resulted in a 89.4 meter benefit compared to patients in our placebo/delayed treatment arm, those patients who received placebo for 24 weeks followed by 24 weeks of treatment with eteplirsen in the open-label extension of the study.

Upon evaluating all study participants through 48 weeks, no treatment-related adverse events which further demonstrate the highly favorable safety profile of eteplirsen.

An abstract describing the results from this Phase IIb extension study has been accepted as part of the World Muscle Society (WMS) Congress's Late-Breaking Science program in Perth, Australia during October 9 to October 13, 2012.

Principal investigator, Jerry R. Mendell, M.D. of Nationwide Children's Hospital, will present the data "Results at 48 Weeks of a Phase IIb Extension Study of the Exon-Skipping Drug Eteplirsen in Patients with Duchenne muscular dystrophy (DMD)" at the World Muscle Society (WMS) Congress's Late-Breaking Science program in Perth, Australia on October 13 at 4:00 p.m. WST UTC +8 hours/4:00 a.m. EDT.

Summary of Dystrophin: Eteplirsen-Treated Patients in All Dose Groups through Week 48*

Treatment Arm			Mean Change from Baseline in % Dystrophin-Positive Fibers		p-value
Eterplirsen (both doses): 48 wks of Tx (n=8)			47.0		≤0.001
	Eteplirsen 50 mg/kg (n=4)		41.7		≤0.008
	Eteplirsen 30 mg/kg (n=4)		52.1		≤0.001
Placebo/Delayed Tx: 24 wks of Tx (n=4)			38.3		≤0.009
	Placebo/50 mg/kg Delayed-Tx (n=2)		42.9		ns
	Placebo/30 mg/kg Delayed-Tx (n=2)		34.2		ns

* Values based on Immunofluorescence using anti-dystrophin antibody MANDYS106

Modified Intent-to-Treat (mITT)

The 6MWT results were further analyzed using the mITT population which excluded two patients who were randomized to the 30 mg/kg weekly eteplirsen cohort who showed signs of rapid disease progression within weeks after enrollment and were unable to perform measures of ambulation beyond 24 weeks. This mITT population consisted of 10 patients (4 eteplirsen-treated patients receiving 50 mg/kg weekly, 2 eteplirsen-treated patients receiving 30 mg/kg weekly, and 4 placebo/delayed-treatment patients).

Summary of 6MWT: Eteplirsen versus Placebo/Delayed-Treatment to Week 48*

Treatment Arm		Mean Change from Baseline in 6MWT (meters)		Estimated Treatment Effect (Eteplirsen minus Placebo/Delayed-Tx)		p-value
Placebo/Delayed-Tx (n=4)		-60.3
Eteplirsen 50 mg/kg (n=4)		+27.1		87.4 m		≤0.001
Eteplirsen Both Doses (n=6)		+7.3		67.3 m		≤0.001
Eteplirsen 30 mg/kg (n=2)		-31.5		28.8 m		ns

*Note: Analysis based on Mixed Model Repeated Measures test

Summary of Additional Sub-Group Analyses at Week 48*

Subset		Mean 6MWT Change from Baseline (meters)		Estimated Treatment Benefit (Eteplirsen minus Placebo/delayed-Tx)		p-value
Placebo/delayed Tx: < 9.5 yrs at baseline (n=2; mean=7.6 yrs)		-42.3		58.9 m		≤0.038
Eteplirsen: < 9.5 yrs at baseline (n=3; mean=8.4 yrs)		+16.5
Placebo/delayed Tx: ≥9.5 yrs at baseline (n=2; mean=10.1 yrs)		-63.5		52.1 m		ns
Eteplirsen: ≥9.5 yrs at baseline (n=3; mean=10.4 yrs)		-11.3
Placebo/delayed Tx: Higher 6MWT baseline (n=2; mean=422m)		-53.5		93.8 m		≤0.001
Eteplirsen: Higher 6MWT baseline (n=3; mean=424m)		+40.3
Placebo/delayed Tx: Lower 6MWT baseline (n=2; mean=367m)		-65.8		39.6 m		ns
Eteplirsen: Lower 6MWT baseline (n=3; mean=375m)		-26.2
Placebo/delayed Tx: Genotype 49-50 deletion (n=3; age mean=9.2 yrs, 6MWT BL mean=397m)		-69.0		83.4 m		≤0.001
Eteplirsen: Genotype 49-50 deletion (n=2; age mean=9.1 yrs, 6MWT BL mean=383m)		+14.4

 * Note: Analysis based on Mixed Model Repeated Measures test

About Study 201 and Study 202 (Phase IIb Eteplirsen Study)

Study 4658-US-201 was conducted at Nationwide Children's Hospital in Columbus, Ohio. Twelve boys meeting the inclusion criteria being between 7 and 13 years of age with appropriate deletions of the dystrophin gene that confirm eligibility for treatment with an exon-51 skipping drug, received double-blind IV infusions of placebo (n=4), 30 mg/kg of eteplirsen (n=4), or 50 mg/kg of eteplirsen once weekly for 24 weeks (n=4). Muscle biopsies for evaluation of dystrophin were obtained at baseline for all subjects, and after 12 weeks for patients in the 50 mg/kg cohort and after 24 weeks for patients in the 30 mg/kg cohort. Two placebo patients were randomized to the 30 mg/kg cohort and two placebo patients were randomized to the 50 mg/kg cohort. This study design allowed to investigate the relationship of dose and duration of eteplirsen treatment on the production of dystrophin over the course of the 24-week study.

Study 4658-US-202 is the extension study to 201 and continues to assess the long-term safety and efficacy of open-label eteplirsen. The four placebo patients were rolled over to open-label eteplirsen at week 24, with six patients on 30 mgs/kg, and six patients on 50 mgs/kg. Third biopsies occurred at 48 weeks in the original study 201 treated patients, and at 24 weeks, the same time point, in the original placebo patients. 6MWT was performed at 32 weeks, 36 weeks, 48 weeks and will continue to be performed every 12 weeks going forward.

About Dystrophin
Dystrophin, a large structural protein, is critical to the stability of myofiber membranes in skeletal, diaphragmatic and cardiac muscle, protecting muscle fibers from contraction-induced damage. Loss of functional dystrophin destabilizes the dystroglycan protein complex, impairing its localization to the muscle membrane, and compromising the integrity of the membrane structure. The absence of functional dystrophin results in muscle membrane breakdown with muscle fibers being replaced by adipose and fibrotic tissue.

Eteplirsen

Eteplirsen uses phosphorodiamidate morpholino oligomer (PMO)-based chemistry and proprietary exon-skipping technology to skip exon 51 of the dystrophin gene enabling the repair of specific genetic mutations that affect approximately 13 percent of the total DMD population. By skipping exon 51, eteplirsen may restore the gene's ability to make a shorter, but still functional, form of dystrophin from messenger RNA, or mRNA. Promoting the synthesis of a truncated dystrophin protein is intended to improve, stabilize or significantly slow the disease process and prolong and improve the quality of life for patients with DMD.

About the 6-Minute Walk Test
The 6-minute walk test (6MWT) was developed as an integrated assessment of cardiac, respiratory, circulatory, and muscular capacity (American Thoracic Society 2002) for use in clinical trials of various cardiac and pulmonary conditions.

In recent years the 6MWT has been adapted to evaluate functional capacity in neuromuscular diseases and has served as the basis for regulatory approval of a number of drugs for rare diseases, with mean changes in the 6MWT ranging from 28 to 44 meters (Rubin 2002, Wraith 2004, Muenzer 2006).

Additionally, published data from longitudinal natural history studies assessing dystrophinopathy, a disease continuum comprised of DMD and Becker muscular dystrophy, support the utility of the 6MWT as a clinically meaningful endpoint (McDonald C, et al, Muscle & Nerve, December 2010) in DMD.

These data show that boys with DMD experience a significant decline in walking ability compared to healthy boys over one year, suggesting that slowing the loss of walking ability is a major treatment goal.

About the Statistical Methodology

The Mixed Model Repeated Measures (MMRM) test was used for all statistical analyses of the 6MWT results, including for all subgroups. Analysis of Covariance (ANCOVA) for ranked data was used when the assumptions of normality of the dependent variable (the change in 6MWT distance from baseline) were violated.

The inclusion of the two patients with extreme scores due to rapid progression in the ITT population (n=12) resulted in a violation of the normality assumptions of the Change from Baseline in 6MWT data, and thus required the use of ANCOVA for ranked data.

The exclusion of these two patients from the mITT population (n=10) resulted in the 6MWT data becoming normally distributed and the MMRM statistics exhibiting much improved residuals and fit statistics as compared to the ITT population.

As such, the estimated mean values and their associated p-values for the mITT population were slightly different from those for the ITT population.

Sources:
SAREPTA
Action Duchenne

Other resources:

SAREPTA will hold a conference call and broadcast a slide show today at 8:00 a.m. EDT (5:00 a.m. PDT) to discuss these results. The audio conference call may be accessed by dialing 866.356.3093 for domestic callers and 617.597.5381 for international callers. The passcode for the call is 93880948. Please specify to the operator that you would like to join the "Sarepta Therapeutics 48-Week Results Call." To view the slide show while using the audio dial-in please go to the events section of Sarepta's website at www.sareptatherapeutics.com. The call and slide show will also be webcast live under the events section and will be archived there following the call for 90 days. Please connect to Sarepta's website several minutes prior to the start of the broadcast to ensure adequate time for any software download that may be necessary. An audio replay will be available through October 10, 2012 by calling 888.286.8010 or 617.801.6888 and entering access code 67898748.

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Published: 04 October 2012

Last Updated: 08 February 2020

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