Post by Andre on Mar 11, 2007 8:35:16 GMT -5
Hi David,
what do you think?
Which of the research is realistic?
When will first be available?
newest research:
- Molecular Sealant -
University of Colorado, Health Sciences Center – Brian Tseng, MD, PhD
Dr. Tseng is developing a “molecular sealant” to patch the holes in the muscles cells of boys with DMD and strengthen the membranes. The sealant, called Poloxamer 407, is approved for use in commonly used mouthwashes and drugs. It is currently undergoing human clinical trials for other diseases. Together with Charley’s Fund, this effort is being supported by the Nash Avery Foundation, the Jett Foundation and Cure Duchenne.
- TAT-Utrophin -
University of Minnesota – James Ervasti, PhD
Dr. Ervasti has come up with a way to transport utrophin -- a protein that can act as a substitute for dystrophin -- to the muscle cells. This approach requires that utrophin is attached to another protein called TAT. This new fused protein (or chimera) is then transported into the cell. Dr. Ervasti has promising preliminary results that demonstrate improvement in a mouse model treated with this therapy. Currently, Dr. Ervasti is investigating the chimera’s optimal dosage, frequency of administration, and mode of delivery.
- Galgt2 -
Columbus Children’s Research Institute – Paul T. Martin, PhD
From previous studies, Dr. Martin concluded that Galgt2, a protein that adds sugars to other proteins, could be a therapeutic target for a treatment for DMD. Mice with muscular dystrophy have a 3-fold increase in natural expression of Galgt2. This observation led Dr. Martin to conclude that Galgt2 overexpression may ameliorate the dystrophic condition. Dr. Martin is now developing a reporter cell line that can be used to screen compounds that would activate the human Galgt2 promoter, thereby causing overexpression of the protein.
- Biglycan -
Brown University – Justin Fallon, PhD.
Utrophin is a compensatory protein that can act as a substitute for dystrophin, the missing protein in DMD boys. Dr. Fallon has discovered that a protein called biglycan can upregulate utrophin expression in a muscular dystrophy mouse model. He has observed other beneficial effects of biglycan, including reduction of muscle fiber cell death. In Dr. Fallon’s previous studies, a single dose of biglycan was effective in the mouse model for three weeks. Dr. Fallon is currently testing biglycan in the mouse model to determine whether mice treated with biglycan show functional improvement.
overview:
--- CALPAIN/PROTEASE INHIBITORS
SNT-MC17 is developed by Santhera Pharmaceuticals AG. Santhera has entered into a proof-of-concept Phase IIa trial with scientists at the University of Leuven (Belgium) to show the effect of SNT-MC17 on cardiomyopathy associated with Duchenne Muscular Dystrophy.
- Myodur is developed by Ceptor Corporation and includes a carnitine carrier molecule and a leupeptin analogue, a known calpain inhibitor. In the MDX mouse model, MYODUR was shown to be as effective as leupeptin alone in preserving muscle tissue. The drug is granted Orphan Drug Status and clinical trials are anticipated in April 2006.
--- ANTI-INFLAMMATORY
Albuterol a.k.a. Ventolin, Proventil is developed by GlaxoSmithKline and falls under the beta-2 agonists category, which is usually used to treat asthma. Pilot study at UCLA, sponsored by MDA showed evidence that Albuterol treatment may increase muscle protein synthesis and slow muscle protein breakdown. There is however a potential risk of heart related side effect as the drug stimulates the receptors of the heart.
- Cyclosporine A is developed by Novartis and is widely used to prevent organ rejections during transplantation. In DMD, it can potentially slow down muscle degeneration through inhibition of production of T lymphocytes. It is currently undergoing a Phase I/II study in Germany for DMD.
- Pentoxifillin is a mast cell stabilizer and is currently being investigated for its degeneration inhibition qualities in University of Pennsylvania under the supervision of Dr. H. Lee Sweeney, professor of physiology. Phase I/II studies are in progress at The Cooperative International Neuromuscular Research Group (CINRG).
- NFkappaB agents would stabilize the
NFkappaB pathway to enhance survival and improve resting membrane potential. There are, however, concerns that these agents maybe toxic with chronic administration. Animal studies are currently ongoing with no set date for clinical trials in humans.
- nNos upregulation is being investigated by Judy Anderson, Ph.D. at the Department of Human Anatomy and Cell Science at University of Manitoba. The background of the process is that the absence of dystrophin, results in a cascade of pathological and biochemical processes, including the decreasing of Nitric Oxide Synthase (nNos). The loss of nNos causes vascular constriction, thus decreasing blood supply and oxygen to the muscle. Anticipated result of the upregulation is the slow down of muscle degeneration.
Remicade is developed by Centocor as a TNF inhibitor. Animal studies on the MDX mouse conducted in University of Western Australia showed that inhibition of TNF activity with Remicade delayed and greatly reduced the breakdown of dystrophic muscle.
--- GROWTH FACTORS
IGF-1 is a growth factor that stimulates the differentiation and proliferation of myoblasts as well as the amino acid uptake and protein synthesis in muscles and other tissues. A Phase III studies for amyotrophic lateral sclerosis has recently completed. DMD trials are not planned at this time.
- MYO-029 is being developed by Wyeth-Ayerst. MYO-029 is expected to inhibit the production of myostatin (a negative regulator of muscle size) in the body and increase the overall muscle mass of DMD patients. Phase I/II clinical trials are currently in progress for adult patients with facioscapulohumeral MD (FSHD), Becker MD (BMD) and limb-girdle MD (LGMD).
--- INDUCING PRODUCTION OF DYSTROPHIN
PTC124 is a first-in-class, orally delivered, investigational new drug for the treatment of genetic disorders resulting from nonsense mutations. Developed by PTC Therapeutics, PTC124 is a unique drug that allows the ribosomal cellular machinery to bypass the premature termination codon in the messenger RNA and continue the translation process, restoring the production of full-length, functional protein. The drug is currently going through Phase II of clinical trials.
--- GENE CORRECTION
- Exon Skipping therapy is sponsored by Prosensa and based on muscle injections into the arms and legs which could potentially produced a shortened version of dystrophin, stabilize the muscles and slow or even stop muscle degeneration. Phase I/II trials are expected in the first quarter of 2006.
- MyoDys is being developed by Transgene, and is an improved version, 24 kb large plasmid carrying the full-length human dystrophin cDNA under the control of a proprietary muscle-specific promoter allowing strong, smooth, skeletal and cardiac muscle restricted expression. This program, which aims at replacing the defective gene in the diseased muscles, is being financed by the French Muscular Dystrophy Association (AFM).
--- GENE THERAPY
Adeno-Associated Virus (AAV) Micro Dystrophin is comprised of small non-enveloped single stranded DNA viruses. Eight serological strains have been described among humans and primates. In human, AAV infection is not associated with any disease, and its persistence in the human organism is asymptomatic. This favorable non-pathogenic profile makes AAV very attractive tools for gene therapy in humans. Asklepios BioPharmaceutical, Inc. are currently developing this approach.
--- CORTICOSTEROIDS
Prednisone and Deflazacort are beneficial in the treatment of DMD. Seven high-quality studies showed a significant increase in strength, timed muscle function (such as time to climb stairs) and pulmonary function with these medications.
--- NEW DRUG DISCOVERY (HIGH THROUGHPUT SCREENS)
- Project Catalyst is a collaborative project between PTC Therapeutics and Parent Project Muscular Dystrophy. The goal of the collaboration is to identify small molecule compounds that can be developed into novel drugs for the treatment of DMD.
- Genzyme does extensive research in the field of genetic disorders. Their Duchenne Muscular Dystrophy program is in the initial stage of development.
- UCLA is currently running high throughput screens on specific targets such as: muscle membrane stabilizers, anti-inflammatory agents, anti-fibrosis agents as well as upregulation of NFAT/calcineurin pathway.
- VASTox has successfully done in-vivo the upregulation of utrophin. This proteing has been demonstrated to replace the function of dystrophin, which is missing in DMD patients and helps keep muscle cells intact. The selection of a clinical candidate is scheduled for 2007.
Yours sincerely,
André
what do you think?
Which of the research is realistic?
When will first be available?
newest research:
- Molecular Sealant -
University of Colorado, Health Sciences Center – Brian Tseng, MD, PhD
Dr. Tseng is developing a “molecular sealant” to patch the holes in the muscles cells of boys with DMD and strengthen the membranes. The sealant, called Poloxamer 407, is approved for use in commonly used mouthwashes and drugs. It is currently undergoing human clinical trials for other diseases. Together with Charley’s Fund, this effort is being supported by the Nash Avery Foundation, the Jett Foundation and Cure Duchenne.
- TAT-Utrophin -
University of Minnesota – James Ervasti, PhD
Dr. Ervasti has come up with a way to transport utrophin -- a protein that can act as a substitute for dystrophin -- to the muscle cells. This approach requires that utrophin is attached to another protein called TAT. This new fused protein (or chimera) is then transported into the cell. Dr. Ervasti has promising preliminary results that demonstrate improvement in a mouse model treated with this therapy. Currently, Dr. Ervasti is investigating the chimera’s optimal dosage, frequency of administration, and mode of delivery.
- Galgt2 -
Columbus Children’s Research Institute – Paul T. Martin, PhD
From previous studies, Dr. Martin concluded that Galgt2, a protein that adds sugars to other proteins, could be a therapeutic target for a treatment for DMD. Mice with muscular dystrophy have a 3-fold increase in natural expression of Galgt2. This observation led Dr. Martin to conclude that Galgt2 overexpression may ameliorate the dystrophic condition. Dr. Martin is now developing a reporter cell line that can be used to screen compounds that would activate the human Galgt2 promoter, thereby causing overexpression of the protein.
- Biglycan -
Brown University – Justin Fallon, PhD.
Utrophin is a compensatory protein that can act as a substitute for dystrophin, the missing protein in DMD boys. Dr. Fallon has discovered that a protein called biglycan can upregulate utrophin expression in a muscular dystrophy mouse model. He has observed other beneficial effects of biglycan, including reduction of muscle fiber cell death. In Dr. Fallon’s previous studies, a single dose of biglycan was effective in the mouse model for three weeks. Dr. Fallon is currently testing biglycan in the mouse model to determine whether mice treated with biglycan show functional improvement.
overview:
--- CALPAIN/PROTEASE INHIBITORS
SNT-MC17 is developed by Santhera Pharmaceuticals AG. Santhera has entered into a proof-of-concept Phase IIa trial with scientists at the University of Leuven (Belgium) to show the effect of SNT-MC17 on cardiomyopathy associated with Duchenne Muscular Dystrophy.
- Myodur is developed by Ceptor Corporation and includes a carnitine carrier molecule and a leupeptin analogue, a known calpain inhibitor. In the MDX mouse model, MYODUR was shown to be as effective as leupeptin alone in preserving muscle tissue. The drug is granted Orphan Drug Status and clinical trials are anticipated in April 2006.
--- ANTI-INFLAMMATORY
Albuterol a.k.a. Ventolin, Proventil is developed by GlaxoSmithKline and falls under the beta-2 agonists category, which is usually used to treat asthma. Pilot study at UCLA, sponsored by MDA showed evidence that Albuterol treatment may increase muscle protein synthesis and slow muscle protein breakdown. There is however a potential risk of heart related side effect as the drug stimulates the receptors of the heart.
- Cyclosporine A is developed by Novartis and is widely used to prevent organ rejections during transplantation. In DMD, it can potentially slow down muscle degeneration through inhibition of production of T lymphocytes. It is currently undergoing a Phase I/II study in Germany for DMD.
- Pentoxifillin is a mast cell stabilizer and is currently being investigated for its degeneration inhibition qualities in University of Pennsylvania under the supervision of Dr. H. Lee Sweeney, professor of physiology. Phase I/II studies are in progress at The Cooperative International Neuromuscular Research Group (CINRG).
- NFkappaB agents would stabilize the
NFkappaB pathway to enhance survival and improve resting membrane potential. There are, however, concerns that these agents maybe toxic with chronic administration. Animal studies are currently ongoing with no set date for clinical trials in humans.
- nNos upregulation is being investigated by Judy Anderson, Ph.D. at the Department of Human Anatomy and Cell Science at University of Manitoba. The background of the process is that the absence of dystrophin, results in a cascade of pathological and biochemical processes, including the decreasing of Nitric Oxide Synthase (nNos). The loss of nNos causes vascular constriction, thus decreasing blood supply and oxygen to the muscle. Anticipated result of the upregulation is the slow down of muscle degeneration.
Remicade is developed by Centocor as a TNF inhibitor. Animal studies on the MDX mouse conducted in University of Western Australia showed that inhibition of TNF activity with Remicade delayed and greatly reduced the breakdown of dystrophic muscle.
--- GROWTH FACTORS
IGF-1 is a growth factor that stimulates the differentiation and proliferation of myoblasts as well as the amino acid uptake and protein synthesis in muscles and other tissues. A Phase III studies for amyotrophic lateral sclerosis has recently completed. DMD trials are not planned at this time.
- MYO-029 is being developed by Wyeth-Ayerst. MYO-029 is expected to inhibit the production of myostatin (a negative regulator of muscle size) in the body and increase the overall muscle mass of DMD patients. Phase I/II clinical trials are currently in progress for adult patients with facioscapulohumeral MD (FSHD), Becker MD (BMD) and limb-girdle MD (LGMD).
--- INDUCING PRODUCTION OF DYSTROPHIN
PTC124 is a first-in-class, orally delivered, investigational new drug for the treatment of genetic disorders resulting from nonsense mutations. Developed by PTC Therapeutics, PTC124 is a unique drug that allows the ribosomal cellular machinery to bypass the premature termination codon in the messenger RNA and continue the translation process, restoring the production of full-length, functional protein. The drug is currently going through Phase II of clinical trials.
--- GENE CORRECTION
- Exon Skipping therapy is sponsored by Prosensa and based on muscle injections into the arms and legs which could potentially produced a shortened version of dystrophin, stabilize the muscles and slow or even stop muscle degeneration. Phase I/II trials are expected in the first quarter of 2006.
- MyoDys is being developed by Transgene, and is an improved version, 24 kb large plasmid carrying the full-length human dystrophin cDNA under the control of a proprietary muscle-specific promoter allowing strong, smooth, skeletal and cardiac muscle restricted expression. This program, which aims at replacing the defective gene in the diseased muscles, is being financed by the French Muscular Dystrophy Association (AFM).
--- GENE THERAPY
Adeno-Associated Virus (AAV) Micro Dystrophin is comprised of small non-enveloped single stranded DNA viruses. Eight serological strains have been described among humans and primates. In human, AAV infection is not associated with any disease, and its persistence in the human organism is asymptomatic. This favorable non-pathogenic profile makes AAV very attractive tools for gene therapy in humans. Asklepios BioPharmaceutical, Inc. are currently developing this approach.
--- CORTICOSTEROIDS
Prednisone and Deflazacort are beneficial in the treatment of DMD. Seven high-quality studies showed a significant increase in strength, timed muscle function (such as time to climb stairs) and pulmonary function with these medications.
--- NEW DRUG DISCOVERY (HIGH THROUGHPUT SCREENS)
- Project Catalyst is a collaborative project between PTC Therapeutics and Parent Project Muscular Dystrophy. The goal of the collaboration is to identify small molecule compounds that can be developed into novel drugs for the treatment of DMD.
- Genzyme does extensive research in the field of genetic disorders. Their Duchenne Muscular Dystrophy program is in the initial stage of development.
- UCLA is currently running high throughput screens on specific targets such as: muscle membrane stabilizers, anti-inflammatory agents, anti-fibrosis agents as well as upregulation of NFAT/calcineurin pathway.
- VASTox has successfully done in-vivo the upregulation of utrophin. This proteing has been demonstrated to replace the function of dystrophin, which is missing in DMD patients and helps keep muscle cells intact. The selection of a clinical candidate is scheduled for 2007.
Yours sincerely,
André
