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Category Archives: Muscular Dystrophy Treatment
Posted: September 6, 2017 at 5:44 pm
Shares of Sarepta Therapeutics soared 12 percent in early trading Wednesday after the biopharmaceutical company reported positive results from a clinical trial of an experimental medicine for Duchenne muscular dystrophy.
The drug, golodirsen, would be Sarepta’s second to treat the rare, genetic disease, which causes muscle wasting and can be fatal before patients turn 30. Sarepta focuses on the discovery and development of precision genetic medicines to treat rare neuromuscular diseases.
The new study, conducted in Europe, involved 25 boys with confirmed deletions of the DMD gene amenable to skipping exon 53. Exons are part of the DNA code. The treatment targets a genetic mutation affecting about 8 percent of patients with DMD.
Sarepta’s first drug for DMD, Exondys 51 approved on a conditional basis by the FDA last year pending more testing to confirm results treats a mutation affecting about 13 percent. Exondys 51 costs about $300,000 per year.
“Our goal is to treat 100 percent” of DMD suffers, Sarepta CEO Doug Ingram told CNBC’s “Squawk Box.” “The data that we have this morning shows we’re on the right path.”
The results, announced before Wall Street’s open bell, showed that golodirsen increased production of the protein dystrophin to 1.02 percent of normal levels from about 0.095 percent without the drug. Analysts said those results were higher than expected, but scientists wonder whether that’s enough to increase muscle strength and have a clinical benefit.
According to Sarepta, the underlying cause of DMD is a mutation in the gene for dystrophin, which is an essential protein involved in muscle fiber function. DMD occurs in one in every 3,500 to 5,000 males worldwide. Symptoms usually start in early childhood, usually between 3- and 5-years old. It primarily affects boys. But in rare cases can affect girls.
“Sarepta is a small company. We have already invested $1 billion fighting Duchenne muscular dystrophy. And we’re not done yet,” said Ingram, who was appointed as CEO in July. Ahead of Wednesday, Sarepta had a stock market value of $2.6 billion.
Mid-Afternoon Market Update: Crude Oil Up Over 1%; Sarepta Shares Jump After Positive Results In DMD Treatment … – Benzinga
Posted: at 5:44 pm
Toward the end of trading Wednesday, the Dow traded up 0.42 percent to 21,845.34 while the NASDAQ climbed 0.41 percent to 6,401.95. The S&P also rose, gaining 0.42 percent to 2,468.27.
Leading and Lagging Sectors
Wednesday afternoon, the energy shares surged 1.23 percent. Meanwhile, top gainers in the sector included Frontline Ltd. (NYSE: FRO), up 5 percent, and JA Solar Holdings Co., Ltd. (ADR) (NASDAQ: JASO), up 6 percent.
In trading on Wednesday, utilities shares fell 0.25 percent. Meanwhile, top losers in the sector included NRG Energy Inc (NYSE: NRG), down 3 percent, and Entergy Corporation (NYSE: ETR) down 1 percent.
G-III Apparel Group, Ltd. (NASDAQ: GIII) reported stronger-than-expected results for its second quarter and raised its FY18 forecast.
G-III Apparel reported a Q2 adjusted loss of $0.15 per share on revenue of $538 million. However, analysts were expecting a loss of $0.26 per share on sales of $522 million.
Equities Trading UP
Verastem Inc (NASDAQ: VSTM) shares shot up 30 percent to $5.00 after the company disclosed that its Phase 3 DUO study evaluating the efficacy and safety of duvelisib showed statistically significant improvement.
Shares of Voyager Therapeutics Inc (NASDAQ: VYGR) got a boost, shooting up 20 percent to $13.10 after the company announced ‘positive’ results from ongoing Phase 1b trial of VY-AADC01 for advanced Parkinson’s disease.
Sarepta Therapeutics Inc (NASDAQ: SRPT) shares were also up, gaining 16 percent to $47.52 following the announcement of positive results in its study for the treatment of Duchenne Muscular Dystrophy.
Equities Trading DOWN
Trivago NV – ADR (NASDAQ: TRVG) shares dropped 18 percent to $12.29 after the company lowered its guidance.
Shares of At Home Group Inc (NYSE: HOME) were down 10 percent to $23.19. At Home Group reported Q2 adjusted earnings of $0.18 per share on revenue of $232.1 million.
Dave & Buster’s Entertainment, Inc. (NASDAQ: PLAY) was down, falling around 10 percent to $52.38. Dave & Buster’s posted upbeat earnings for its second quarter, while sales missed expectations. The company also cut its comparable-store sales forecast for its fiscal year.
In commodity news, oil traded up 1.07 percent to $49.18 while gold traded down 0.42 percent to $1,338.90.
Silver traded down 0.03 percent Wednesday to $17.935, while copper rose 0.83 percent to $3.154.
European shares closed mostly higher today. The eurozones STOXX 600 rose 0.06 percent, the Spanish Ibex Index declined 0.48 percent, while Italys FTSE MIB Index gained 0.35 percent. Meanwhile the German DAX climbed 0.75 percent, and the French CAC 40 rose 0.29 percent while U.K. shares fell 0.25 percent.
The MBAs index of mortgage application activity rose 3.3 percent for the latest week.
The U.S. trade deficit rose to $43.7 billion in July, compared to $43.5 billion in June. However, economists were expecting a $44.8 billion deficit. Imports declined 0.2 percent to $238.1 billion in July, while exports dropped 0.3 percent to $194.4 billion.
The Johnson Redbook Retail Sales Index rose 0.3 percent during the first week of September versus August.
The ISM non-manufacturing index climbed to 55.30 in August, versus prior reading of 53.90. Economists projected a reading of 55.40.
The Federal Open Market Committee released its latest Beige Book report.
Posted-In: Mid-Afternoon Market UpdateNews Eurozone Commodities Global Intraday Update Markets
2017 Benzinga.com. Benzinga does not provide investment advice. All rights reserved.
Posted: at 5:44 pm
Check out which companies are making headlines before the bell:
Exxon Mobil UBS upgraded the stock to “neutral” from “sell,” noting the underperformance of the stock this year and an improved macro outlook for the oil industry.
Sarepta Therapeutics The drugmaker announced positive study results for a new treatment for Duchenne Muscular Dystrophy.
Navistar The truck and engine maker earned 37 cents per share for its latest quarter, beating estimates by nine cents a share. Revenue also topped forecasts. The return to profitability for Navistar comes as it increases market share and profit margins.
HD Supply Holdings The industrial distributor matched forecasts with adjusted quarterly profit of 64 cents per share, with revenue very slightly above Street projections.
Newell Brands The consumer products maker cut its full-year forecast, due to the impact of Hurricane Harvey on its resin suppliers. Newell’s Rubbermaid division is among its substantial users of resins.
Trivago The travel website operator cut its full-year outlook, based on slower-than-expected revenue growth. Trivago said revenue per qualified referral a key metric fell too quickly to prevent overspending on ad purchases.
G-III Apparel The manufacturer of licensed apparel lost 18 cents per share for its latest quarter, eight cents a share less than analysts had anticipated. Revenue beat forecasts and G-III raised its full-year forecast. The company said strong brand names like Tommy Hilfiger and Calvin Klein are helping it overcome significant marketplace headwinds.
Hewlett Packard Enterprise The enterprise technology company reported adjusted quarterly profit of 30 cents per share, beating estimates by four cents a share. Revenue easily beat forecasts on the strength of improved networking equipment sales.
Dave & Buster’s Dave & Buster’s beat estimates by two cents a share, with adjusted quarterly profit of 59 cents per share. The restaurant chain’s revenue fell below forecasts and it also cut full-year comparable restaurant sales guidance.
Wal-Mart The retailer kicked off its holiday layaway plan, hoping to provide a boost to slow toy sales. Under the program, customers can put as little as $10 down to hold items with a minimum sales price of $50.
Novo Nordisk Novo Nordisk settled a Food and Drug Administration (FDA) investigation into its diabetes drug Victoza. The Danish drugmaker will pay about $58.7 million to resolve claims that it downplayed FDA-mandated warnings about the cancer risks for users of the treatment.
Royal Caribbean, Carnival, Norwegian Cruise Line Cruise line stocks are on watch once again after falling the past two sessions on concerns about the financial impact of Hurricanes Harvey and Irma. Also on hurricane watch: airline stocks, including American Airlines, United Continental, Delta Air Lines, and Southwest Airlines, among others.
MGM Resorts MGM announced a $1 billion stock buyback program, and also said it would sell the MGM National Harbor casino’s real estate to MGM Growth Properties for $1.19 billion. MGM Resorts will continue to operate that property.
Duluth Holdings Duluth reported quarterly profit of 13 cents per share, three cents a share above estimates. The casual wear company also saw revenue exceed forecasts. The parent of Duluth Trading saw a better than 30 percent improvement in net sales over a year earlier, as it opened more stores and attracted new customers.
Fiat Chrysler The automaker was upgraded to “overweight” from “equal-weight” at Barclays, as speculation continues about the possible sale of the Jeep division or the company as a whole.
Go here to read the rest:
Early movers: XOM, SRPT, NAV, HDS, NWL, TRVG, GIII, HPE & more – CNBC
Posted: at 5:44 pm
A single gene therapy that silences the mutation responsible for oculopharyngeal muscular dystrophy (OPMD) and replaces the mutated gene with a normal one may advance into human studies in the second half of 2018.
Benitec Biopharma started its OPMD program in 2014 and now announced their clinical candidate BB-301 as a one-step gene therapy approach.
OPMD patients develop muscle weakness in the upper eyelids and throat in adulthood, typically after age 40. OMPD is a rare genetic disease caused by a mutation of the poly(A)-binding protein nuclear 1 (PABPN1) gene. Because it affects fewer than 200,000 people nationwide, OMPD is considered an orphan disease that benefits from encouraging programs for drugs targeting these rare diseases.
In collaboration with research groups in London and Paris, Benitec tested a genetic approach known as DNA-directed RNA interference (ddRNAi) to shut down and replace the mutant PABPN1 gene using two different viral vectors. In this pre-clinical study, researchers found that the two-vector system restored muscular function in A17 mouse model, which displays many OPMD clinical signs including fibrosis and loss of muscle strength.
Now, Benitec combined silence and replace gene functions into a single vector (a carrier system) ina new clinical candidate, BB-301. Using a single vector, they succeed in eliminating 88 percent of the mutant gene product while restoring the normal gene function up to 90 percent. As a single product, BB-301 simplifies the regulatory process and the clinical strategy for human studies.
This is an important development in our OPMD program. The single vector system shows the same excellent activity as the earlier generation dual vector system where the silence and replace constructs were delivered in separate vectors. Similar application of the single vector technology may allow development of novel therapeutics to treat other orphan diseases. OPMD is a significant commercial opportunity for Benitec and we are working with the regulators and key opinion leaders in this field to advance BB-301 into the clinic as quickly as possible, Greg West, CEO, explained in a press release.
Benitec is in discussions with a broad group of OPMD clinicians and experts about a clinical trial that will be proposed to regulatory agencies later this year. If approved by the U.S. Food and Drug Administration, human studies could start in 2018.
Lynchburg firefighters have boots on the ground to fill the boot for muscular dystrophy – Lynchburg News and Advance
Posted: at 9:42 pm
This year, collecting donations to go toward research for treating muscular dystrophy during the Lynchburg Fire Departments Fill the Boot campaign has a different meaning for David Cox.
Cox had worked for the department for more than 15 years but retired at the beginning of August after he was diagnosed with Myasthenia Gravis, a neuromuscular disease, at the end of May. Like other muscular dystrophy-related diseases, Myasthenia Gravis weakens muscles as an autoimmune disease that damages connections between nerves and muscles, according to the Muscular Dystrophy Association. Hed participated in the departments fundraisers for the Muscular Dystrophy Association for years and decided to come back post-retirement to help out again this year.
It really does mean more now, you know, he said. Out here today, my legs were shaking this morning I was like, I dont know if Im going to do it, but I said, Why not? Its for a good cause. I can suck it up for three or four hours and just do it.
Some days, Cox said he can only take a few steps before becoming exhausted and needing to rest 10 to 15 minutes, whereas he was able to exercise normally before starting to get sick.
Ive seen both sides of the spectrum Ive seen people who are in worse shape than I am and people that are in better shape than I am and its because of the donations from these folks going to this research, he said. Im first hand, and I can see that its working because without the medicines, I wouldnt be standing here right now.
Although he retired from the Lynchburg Fire Department, Cox also has volunteered with the Altavista Fire Company. With his own medications costing hundreds of dollars per month, he said the decreased financial burden on those with muscular dystrophy, the research and opportunities for free childrens summer camp sessions are worthwhile donations that hes seen at work.
Lynchburg firefighters started out stationed around city shopping centers and watering holes to collect money Monday and will keep at it until Sunday. Cox stood outside the Wards Road Walmart on Tuesday afternoon collecting money alongside a handful of firefighters from the Fort Avenue station. Fire Capt. Matt Smith said personnel had collected a decent chunk of change Monday over a relatively short period of time with boots in hand.
Smith and the others were in and out of the entrance into the stores between calls, since theyre still on duty. Others from their station were out by the Wards Road Target store, since Smith said they want to be visible during peak hours when they know people will be out and about. Their station has a bit of leg up with firefighters collecting from their first due area, within which theyre expected to respond to emergencies first, they have shopping and Liberty University traffic to ask for donations.
We always want to beat our previous years totals, but every penny goes to helping, so well take whatever is given, Smith said.
Lynchburgs Fill the Boot collected about $22,000 in 2016, according to fire department Capt. Abbey Johnston, who coordinates the departments collections for the Muscular Dystrophy Association.
The fire department has been working up to the amounts theyd raised years ago, when they could stand in intersections with the boots. When Lynchburg ordinances changed in the mid-2000s to restrict panhandling, both Johnston and Smith said their collection took a dent. Now, the department has to get permission from businesses to collect.
It took us a while to figure out how to adjust from not being in the streets; of course, this is much safer for us, Smith said.
This years fundraising for the association will accompany proceeds from the departments sale of the Women of the LFD calendar, an effort Johnson put together. Between the calendar and Fill the Boot efforts, she said the department hopes to surpass previous years donations.
Summit Announces Positive Top-Line Data From an Exploratory Phase 2 Clinical Trial Supporting Ridinilazole as a … – GlobeNewswire (press release)
Posted: at 9:42 pm
OXFORD, United Kingdom, Sept. 05, 2017 (GLOBE NEWSWIRE) — Summit Therapeutics plc (NASDAQ:SMMT) (AIM:SUMM), the drug discovery and development company advancing therapies for Duchenne muscular dystrophy and Clostridium difficile infection (CDI), today announces positive top-line data from an exploratory Phase 2 clinical trial that support ridinilazole as a highly selective and potent antibiotic product candidate for the treatment of CDI. In the Phase 2 clinical trial, ridinilazole preserved the gut microbiome of CDI patients to a greater extent than the marketed narrow-spectrum antibiotic, fidaxomicin. During the trials ten-day treatment period, ridinilazole treatment had markedly less impact on the gut microbiome of trial patients by measures of overall diversity and changes in key bacterial families, when compared to those trial patients dosed with fidaxomicin.
In the trial, ridinilazole and fidaxomicin both reduced the abundance of C. difficile. However, fidaxomicin-treated patients had reduced abundancy of other bacterial families associated with microbiome health. For a number of these bacterial families, the difference between the two treatments was statistically significant. Another measure of microbiome health is alpha diversity as measured by the Simpsons Diversity Index. There was a greater reduction in alpha-diversity during fidaxomicin treatment compared with ridinilazole-treated patients. These measures were a key secondary endpoint of the clinical trial and provide additional evidence of ridinilazoles precision in killing C. difficile while preserving the gut microbiome. The primary endpoint of the trial was safety, as measured by the number of treatment emergent adverse events and serious adverse events. During the trial, no new or unexpected safety signals were identified and ridinilazole was well-tolerated.
We increasingly recognise the importance of a healthy and diverse gut microbiome for protection against recurrent CDI, which is a major challenge in the management of the disease. These latest clinical findings show ridinilazole better preserved the microbiome of CDI patients than fidaxomicin, the narrowest spectrum antibiotic currently available for CDI, commented Professor Mark Wilcox, Consultant Microbiologist & Head of Microbiology Research & Development at the Leeds Teaching Hospitals NHS Trust, Professor of Medical Microbiology at the University of Leeds, and Public Health England’s Lead on C. difficile in England. Further, these microbiome data are very supportive of ridinilazoles profile as a highly selective antibiotic with the potential to achieve a meaningful improvement in clinical outcomes for CDI patients.
The exploratory open-label Phase 2 clinical trial enrolled 27 patients aged between 18 and 90 years at trial sites in the US, the UK and the Czech Republic. Patients were randomly assigned to receive either ridinilazole (200mg, twice a day) or fidaxomicin (200mg, twice a day) for ten days. The trial population was unbalanced with more patients randomised to ridinilazole at higher risk of poorer clinical outcomes as measured by ATLAS score, and also with predisposing factors for recurrent CDI.
A secondary endpoint of sustained clinical response (SCR), defined as clinical cure at the end of treatment and no recurrence of CDI within the next 30 days, was achieved in seven of 14 ridinilazole treated patients and six of 13 fidaxomicin treated patients. The trial was not designed for efficacy comparisons due to the small number of patients.
Dr David Roblin, Chief Medical and Operating Officer of Summit added, Ridinilazole is a precision antibiotic that is designed to selectively target C. difficile while being highly preserving of the gut microbiome that plays a crucial role in naturally protecting against recurrent CDI. Ridinilazole has now provided evidence of its high selectivity in two complementary clinical trials. The data from our earlier Phase 2 trial showed a greater microbiome preservation of ridinilazole-treated patients compared with the current standard of care, vancomycin, which led to achieving statistical superiority in sustained clinical response. We believe ridinilazole has the potential to become a front-line therapy for CDI and look forward to initiating Phase 3 clinical trials in the first half of 2018.
More detailed findings from this trial are expected to be presented at an upcoming international infectious disease conference. The results build on positive data from a Phase 2 proof of concept trial of ridinilazole that were published in The Lancet Infectious Diseases in April 2017. Ridinilazole is currently being prepared for Phase 3 clinical trials that are planned to commence in the first half of 2018.
AboutC. difficileInfectionC. difficileinfection is a serious healthcare threat in hospitals, long-term care homes and increasingly the wider community with over one million estimated cases of CDI each year inthe United StatesandEurope. It is caused by an infection of the colon by the bacteriumC. difficile, which produces toxins that cause inflammation and severe diarrhoea, and in the most serious cases can be fatal. Patients typically develop CDI following the use of broad-spectrum antibiotics that can cause widespread damage to the natural gastrointestinal (gut) flora and allow overgrowth ofC. difficilebacteria. Existing CDI treatments are predominantly broad spectrum antibiotics, and these cause further damage to the gut flora and are associated with high rates of recurrent disease. Reducing disease recurrence is the key clinical issue as repeat episodes are typically more severe and associated with an increase in mortality rates and healthcare costs. The economic impact of CDI is significant with one study estimating annual acute care costs at$4.8 billionin the US.
About RidinilazoleRidinilazole is a small molecule antibiotic that Summit is developing for the treatment of CDI. In preclinical efficacy studies, ridinilazole exhibited a targeted spectrum of activity that combined a potent bactericidal effect against all clinical isolates ofC. difficiletested with minimal impact on other bacteria that are typically found in the gut microbiome. In a Phase 2 proof of concept trial in CDI patients, ridinilazole showed statistical superiority in sustained clinical response (‘SCR’) rates compared to the standard of care, vancomycin. In that trial, SCR was defined as clinical cure at end of treatment and no recurrence of CDI within 30 days of the end of therapy. Ridinilazole was also shown to be highly preserving of the gut microbiome in the Phase 2 proof of concept trial, which was believed to be the reason for the improved clinical outcome for the ridinilazole-treated patients. Ridinilazole, an orally administered small molecule, has received Qualified Infectious Disease Product (‘QIDP’) designation and has been granted Fast Track designation by the US Food and Drug Administration. The QIDP incentives are provided through the US GAIN Act and include an extension of marketing exclusivity for an additional five years upon FDA approval.
About Summit Therapeutics Summit is a biopharmaceutical company focused on the discovery, development and commercialisation of novel medicines for indications for which there are no existing or only inadequate therapies. Summit is conducting clinical programs focused on the genetic disease Duchenne muscular dystrophy and the infectious disease C. difficile infection. Further information is available at http://www.summitplc.comand Summit can be followed on Twitter (@summitplc).
For more information, please contact:
Forward-looking StatementsAny statements in this press release about Summits future expectations, plans and prospects, including but not limited to, statements about the clinical and preclinical development of Summits product candidates, the therapeutic potential of Summits product candidates, and the timing of initiation, completion and availability of data from clinical trials, and other statements containing the words “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “plan,” “potential,” “predict,” “project,” “should,” “target,” “would,” and similar expressions, constitute forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including: the uncertainties inherent in the initiation of future clinical trials, availability and timing of data from on-going and future clinical trials and the results of such trials, whether preliminary results from a clinical trial will be predictive of the final results of that trial or whether results of early clinical trials or preclinical studies will be indicative of the results of later clinical trials, expectations for regulatory approvals, availability of funding sufficient for Summits foreseeable and unforeseeable operating expenses and capital expenditure requirements and other factors discussed in the “Risk Factors” section of filings that Summit makes with the Securities and Exchange Commission, including Summits Annual Report on Form 20-F for the fiscal year ended January 31, 2017. Accordingly, readers should not place undue reliance on forward-looking statements or information. In addition, any forward-looking statements included in this press release represent Summits views only as of the date of this release and should not be relied upon as representing Summits views as of any subsequent date. Summit specifically disclaims any obligation to update any forward-looking statements included in this press release.
This announcement contains inside information for the purposes of Article 7 of EU Regulation 596/2014 (MAR).
Europe Limb-Girdle Muscular Dystrophy Market and Competitive Landscape 2017-2021 – Research and Markets – Business Wire (press release)
Posted: at 9:42 pm
DUBLIN–(BUSINESS WIRE)–The “Europe Limb-Girdle Muscular Dystrophy Market and Competitive Landscape – 2017” report has been added to Research and Markets’ offering.
The latest research, Europe Limb-Girdle Muscular Dystrophy Market and Competitive Landscape – 2017, provides comprehensive insights into Limb-Girdle Muscular Dystrophy pipeline, epidemiology, market valuations, product sales, market forecast, product forecasts, and market shares. This study accurately estimates and forecast Limb-Girdle Muscular Dystrophy market size and drug sales. This research also provides insights into Limb-Girdle Muscular Dystrophy epidemiology and late stage pipeline.
The report is classified into nine sections – Limb-Girdle Muscular Dystrophy overview with definitions, symptoms, etiology, diagnosis, treatment options; Limb-Girdle Muscular Dystrophy pipeline insights covering late stage clinical trials pipeline; Limb-Girdle Muscular Dystrophy prevalence trends by countries; Limb-Girdle Muscular Dystrophy market size and forecast by countries, market events, trends; product sales and forecast by countries; market shares by countries. The research scope includes EU5 countries – Germany, France, Italy, Spain, UK, Europe.
Key Topics Covered:
1. Limb-Girdle Muscular Dystrophy: Disease Overview
2. Limb-Girdle Muscular Dystrophy Pipeline Insights
3. Limb-Girdle Muscular Dystrophy Epidemiology Analysis
4. Germany Limb-Girdle Muscular Dystrophy Market Insights
5. France Limb-Girdle Muscular Dystrophy Market Insights
6. Italy Limb-Girdle Muscular Dystrophy Market Insights
7. Spain Limb-Girdle Muscular Dystrophy Market Insights
8. UK Limb-Girdle Muscular Dystrophy Market Insights
9. Europe Limb-Girdle Muscular Dystrophy Market Insights
10. Research Methodology
For more information about this report visit https://www.researchandmarkets.com/research/p2wc2w/europe
Posted: at 9:42 pm
The sequencing of the canine genome along with next generation sequencing technologies like whole exome sequencing have facilitated quicker, easier and more efficient identification of genes and mutations that can cause diseases in dogs. In a study published in Skeletal Muscle researchers have used these technologies to study a form of Limb-girdle muscular dystrophy (muscle wasting and weakness in shoulder and hip muscles) in Boston terriers. Here to tell us about the research and what this means for the breed is lead author of the study Melissa L. Cox.
Melissa L. Cox 5 Sep 2017
Dogs live with humans, and have access to medical care nearly as sophisticated as ours. We are also close in other ways: sharing approximately 85% of our genome that is our complete sets of genes any naturally occurring gene mutation that may cause a disease in dogs is likely to cause a similar condition in humans, and vice versa. Dogs can serve as models of human disease; for example, treatments such as gene therapy can be tried in dogs before going into clinical trials in humans, which can benefit both species.
The sequencing of the canine genome greatly increased the speed and efficiency with which genes that cause disease can be detected. It has also facilitated research into the origin of dogs and the search for genes that underlie specific traits in dogs, such as height and skull shape, and many hereditary diseases. Next generation sequencing (NGS), including whole exome sequencing (WES) technologies which allow geneticists to determine the precise order of nucleotides within DNA and RNA molecules much more quickly and cheaply than before and the establishment of publically available databases has also allowed for easier identification of genes and mutations that may cause disease.
LGMDs are a varied group of Mendelian disorders characterized by muscle wasting and weakness in the muscles of the shoulders and hips
Our group made use of these technologies to study a form of Limb-girdle muscular dystrophy (LGMD) in Boston terrier dogs. LGMDs are a varied group of Mendelian disorders diseases caused by single genes that are inherited according to Mendels laws characterized by muscle wasting and weakness in the muscles of the shoulders and hips. Four affected dogs from three unrelated families were identified by their primary veterinarians, and referred for specialized investigation.
Clinical examination and pathology results confirmed that all affected dogs were suffering from LGMD, and immunohistopathological assays, which use antibodies that bind to certain tissues to reveal their presence, suggested a sarcoglycanopathy that is a disease resulting from mutations in one of four genes that code for a certain type of protein, called a sarcoglycan. Sarcoglycanopathies are autosomal recessive, and have severe symptoms similar to Duchenne muscular dystrophy.
The group originally looked at four Boston terriers affected by LGMD from three unrelated families.
There are six sarcoglycan proteins, four of which (, , , ) are involved in structural and signal functions in muscle. The absence of the sarcoglycans from the muscle of affected dogs made the genes that code for these proteins our candidate genes, and whole exome sequencing allowed us to investigate them simultaneously.
DNA was available from two of the four dogs, and from several relatives of one of the dogs. Whole exome sequencing was performed on a total of 5 dogs, including the two dogs that had the disease and an obligate carrier a dog that didnt have the disease but which had to carry the gene mutation based on analysis of the family history. In one affected dog (Case 3), we found that two nucleotides the buildings blocks of DNA were deleted in one of the sarcoglycan genes. The dogs obligate carrier parent and one other relative each also had one copy of the deletion.
The other affected dog (Case 1) did not share this mutation, which was very surprising to us, given that they were the same breed. Breed structures limit genetic diversity, because dogs are only bred to other dogs of the same breed. This increases the chance that any two dogs will be related, and that they will carry a mutation that is identical by descent, that is, inherited from a shared ancestor. For this reason, most dogs in a breed with the same disease will share the same gene mutation.
This is also a good reminder to the animal breeding and veterinary community that even within one breed, a disease may be caused by more than one mutation
Further analysis showed that Case 1 had a different deletion in the same gene as Case 3. We hypothesize that the dogs have very similar phenotypes because the same portion of the protein coded by the gene is eliminated in the two different mutations.
We screened 200 more Boston terriers from North America and Europe, as well as a large variety of other breeds, and these mutations were not found outside of these two cases and family members. This is good news for the breed, as it appears that these are private mutations, found only in these two families. Although we have developed genetic tests for these two mutations, it will not be necessary for breeders of Boston terriers to add LGMD testing to their routine genetic screening at this time.
This is also a good reminder to the animal breeding and veterinary community that even within one breed, a disease may be caused by more than one mutation. For this reason, it is best practice for testing laboratories to indicate which specific mutation(s) have been tested when writing reports.
The two mutations were found in the sarcoglycan gene SGCD, which has been classified as Limb-girdle muscular dystrophy 2F (LGMD2F) (the number 2 denotes that it is an autosomal recessive gene, while F is the gene name). LGMD2F is the least common form of sarcoglycanopathy in humans, so our report of the first large animal model of sarcoglycanopathy may also be of interest to human medicine.
The work also demonstrates the utility of whole exome sequencing to identify mutations in an extremely small number of affected animals. This allows mutations to be identified more quickly than in the past, as it is not necessary to gather samples from large family groups. The early establishment of a genetic testing program to distinguish between normal and unaffected carrier animals can therefore prevent a disease from unintentionally spreading through a breed population.
Posted: September 2, 2017 at 7:43 am
When Charley Seckler was 3 years old, everyone seemed to notice his big, strong calves. People always said, Charley, youre gonna be a soccer player, his mom, Tracy Seckler, tells PEOPLE.
But when Charleys pediatrician said he might have muscular dystrophy, Tracy began to connect the dots. The concerned mother went online and saw videos of other kids who had her sons same big calves, and they were all using their hands to push themselves off the floor just like her son did. She knew instantly that Charley hadDuchenne muscular dystrophy (DMD).
Duchenne is a rare, progressive, degenerative disease affecting about 1 in 3,500 boys, according to the Muscular Dystrophy Association (MDA). Children with the condition are born without the protein, dystrophin, which results in muscle degeneration. Eventually, they cant walk, feed themselves or breathe on their own. One of the symptoms is enlarged calf muscles because the muscle tissue is abnormal and may contain scar tissue, according to the MDA. Until recently, boys with DMD usually didnt survive beyond their teen years. Life expectancy is increasing and survival into the early 30s is becoming more common.
Tracy and Charley SecklerCourtesy Tracy SecklerAt the time Charley was diagnosed, Tracy who was pregnant with Charleys sister, Maisy, and also mom to Charleys 5-year-old brother, Sam quit her job as a middle school teacher so she could take Charley to doctor appointments in Boston, New York and Washington, D.C.
We thought for sure wed find someone who could help him, says Tracy, 47, of Alford, Massachusetts. You just dont want to hear: Theres nothing we can do.
But all doctors could do was prescribe her son steroids. There was no treatment. There was no cure.
Tracy and her husband, radiologist Dr. Benjy Seckler, were determined to change that. Four months after Charleys diagnosis, they created Charleys Fund to try to save their son.
Charley SecklerCourtesy Tracy SecklerThey spoke to researchers, doctors and scientists and read research papers related to Duchenne. Their first fundraiser, a jewelry auction, raised $60,000. They now sell custom jewelry and ties and even temporary tattoos on their website. They also have a letter writing campaign, an annual scavenger hunt in Central Park and they receive donations from kids lemonade stands.
Over the years, they have directed more than $40 million towards Duchenne research.They even rallied families of kids with Duchenne and co-founded a biotech company that is developing three new drugs.
She really got everybody riveted and to be one voice and to fight for our kids lives, says Kristen Greco, 43 of Neptune, New Jersey, whose 9-year-old son, Luke, has Duchenne.She was really a guiding force. Not just for myself, but the entire Duchenne community.
Kristen Greco and her son, LukeCourtesy Kristen GrecoTracy and her husband have given TED talks and petitioned, lobbied and testified in front of the FDA about new drugs.
Shes quite a visionary, says Duchenne expert Dr. Brenda Wong, Professor of Pediatrics and Neurology and Director, Comprehensive Neuromuscular Center/MDA Clinic at Cincinnati Childrens Hospital Medical Center.Theyve come a long way. She is brilliant. She is really able to be very objective when it comes to analyzing problems and assessing the need.
Last September, a new drug that produces the protein missing in Duchenne patients received FDA approved.
They have really, really put the pressure on therapeutics for Duchennes, says Dr. Louis Kunkle, Professor of Genetics and Pediatrics at Boston Childrens Hospital and Harvard Medical School, who discovered the protein that causes Duchennes in 1987. Its fantastic. Its pushed the field forward.
The FDA-approved drug is tailored to the most common form of Duchenne, and sadly, isnt the kind Charley has. But, there are at least six drugs in human trials, Kunkle says, and more coming.
Its a devastating disorder, Kunkle says. But there is hope on the horizon.
Charley, now 16, is far shorter than his siblings hes 4-foot-2 because the steroids he has taken for 13 years have stunted his growth. Hes the size of a fourth grader, says Tracy. Waitresses give him a kiddie menu and a plastic cup with Mickey Mouse on it.
The Seckler familyCourtesy Tracy SecklerCharley spent the summer working at a coffee shop. He has a map of the world in his room and loves to travel. Hes been everywhere from Tanzania to Paris. He loves sushi, Frank Sinatra and cant stop staring at his new Daniel Wellington watch. A self-proclaimed foodie, he says reading restaurant reviews is his favorite activity.
Charley skied with his family until he was 8 and he had to stop. He can still walk, but they just bought him his first manual wheelchair this summer for when theyre in airports or big cities. Charley was participating in a clinical trial, but it was suspended. Tracy hopes it will restart soon.
Its literally heartbreaking to know that you have to keep waiting especially when every day there is deterioration, Tracy says. Its hard. But theres no way I can give up now.
Shes recently convinced a group of non-profits to fund a clinical trial and is currently planning a global research meeting in Paris.
Shes always busy, Charley says. Im proud of her. Shes always working.
Because she wants to keep him alive.
I want to push as hard as I can, she says. When we first started, I thought to myself, If there could have been a treatment, there woulda been a treatment. But thats not always true. Sometimes you need to ask questions until there are no more questions to ask.