Muscular Dystrophy

Coding Dimension ID: 
302
Coding Dimension path name: 
Muscular Dystrophy

Skeletal muscle development from hESC and its in vivo applications in animal models of muscular dystrophy

Funding Type: 
New Faculty I
Grant Number: 
RN1-00525
ICOC Funds Committed: 
$1 623 064
Disease Focus: 
Muscular Dystrophy
Stem Cell Use: 
Embryonic Stem Cell
Cell Line Generation: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 
Embryonic stem cells (ESC) originating from early stage embryos are able to differentiate into any type of cells in the body. The generation of ESC lines from human embryos (hESC) has attracted a lot of dispute among researchers, but raised the hope that one day hESCs can be used in cell replacement therapy for the treatment of degenerative diseases and cancer. Substantial efforts are currently focused on unveiling the full potential of hESCs by developing culture systems supporting the selective differentiation into the cell types of interest. We have reported the specific culture conditions that allow hESC differentiation in the originator cells (mesenchymal precursors) that form the bones, cartilage and muscles in our body. Furthermore, we then defined the conditions for selective generation of skeletal muscle cells from the hESC-derived mesenchymal precursors. Transplantation of these muscle cells into the limb muscle of immunodeficient mice showed their ability to survive and integrate in the host’s tissue. Muscular dystrophies (MD) are a group of diseases affecting the muscles in our body. MD is characterized by progressive muscle weakness and atrophy for which there is no cure or treatment available. Based on our previous studies, we are proposing to optimize the culture conditions for the in vitro generation of skeletal muscle cells from hESCs and study the developmental mechanisms involved in this process. Furthermore, we will transplant these cells into dystrophic dogs, an animal model of MD, to evaluate their in vivo functionality and potential to repair or replace dystrophic muscle fibers. The accomplishment of our aims will contribute to the understanding of human skeletal muscle development and will provide the basis for the clinical application of hESC-derived cells in muscle diseases.
Statement of Benefit to California: 
The establishment of pluripotent stem cell lines derived from the human blastocyst, hESC, opened a new era in biomedical research. Because of their embryonic origin, hESCs can be virtually differentiated in all the cells of all tissues in our body. There is great hope that in the near future hESC-derived specialized progeny will be used in cell-based therapy for a variety of degenerative diseases and cancer. The California stem-cell initiative, through CIRM, gives a significant boost to hESC research by funding pioneering projects in the field. Muscular dystrophies (MD) are a group of > 20 genetic diseases characterized by progressive weakness and degeneration of the skeletal muscles that control movement. There are many forms of muscular dystrophy, some noticeable at birth (congenital muscular dystrophy) and others in adolescence (Becker and Duchenne MD). Duchenne MD is perhaps the most common form, with a worldwide incidence of 1 in 3,500 male births. This dystrophy occurs as the result of mutations in the gene that regulates dystrophin – a protein involved in maintaining the integrity of muscle fibers. Despite the substantial advances made in identifying the genetic defects causing these diseases, there is no treatment or cure available and affected children usually die in their teens. We propose to investigate the potential clinical applications of hESC-derived skeletal muscle cells upon transplantation in animal models of muscular dystrophy. In parallel, we propose to study the molecular basis of skeletal muscle development during hESC differentiation. This research proposal will benefit the State of California and its citizens in the following ways. First of all, Californians are not immune to any form of MD and the overall incidence of this group of diseases is the same as elsewhere, with devastating consequences for the affected individuals and their families. We already showed that hESC-derived skeletal muscle cells can integrate and survive in a host muscle when transplanted in immunodeficient mice. Therefore, we expect that these cells will efficiently repair dystrophic muscle fibers in animal models of MD, such as dystrophic dogs. If our hypothesis proves to be correct, it is very likely that these cells will be used for transplantations in MD patients. Californians will then be the first to benefit from the outcome of the proposed research. In addition, a successful ESC-based therapy of MD will certainly encourage and stimulate research for other ESC-based therapies for related diseases. In conclusion, the CIRM initiative will undoubtedly lead to the discovery of a therapy and/or the developmental mechanisms leading to some disease. That in itself will put California at the top of ESC research with enormous benefits for all Californians.

A Novel Microenvironment-Mediated Functional Skeletal Muscle from Human Embryonic Stem Cells and their In Vivo Engraftment

Funding Type: 
New Faculty II
Grant Number: 
RN2-00945
ICOC Funds Committed: 
$2 300 569
Disease Focus: 
Muscular Dystrophy
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 
Muscle wasting is a serious clinical problem associated with a number of diseases and health conditions, affecting individuals of all ages. Muscular dystrophy (MD) is a form of muscle wasting disease resulting from genetic mutations. Duchenne muscular dystrophy (DMD) is the most common form of MD that limits motility and life expectancy of children. It is characterized by progressive skeletal muscle degeneration, and occurs in 1 out of every 3,500 male births. Currently, there is no effective treatment to stop or reverse DMD. One of the potential clinical solutions for treating DMD is cell transplantation where the implanted cells contribute to the functional muscle regeneration. Adult stem cells such as mesoangioblasts and AC133 cells have already been shown to ameliorate dystrophic muscle pathology in animals. Although embryonic stem cells (ESCs) can provide unlimited numbers of progenitor cells with the ability to contribute to the formations of functional skeletal muscle, their ability to reverse/repair wasting muscle has not been explored in detail. To this end, we seek to develop an ESC-based cell transplantation therapy for treating muscle-wasting pathology, focusing on DMD. Three specific aims are proposed to achieve this overall goal. (i) Optimize the microenvironment factors comprising of cell-matrix interaction, cytokines, and cell-secreted morphogens on differentiation of ESC into muscle cells using a combinatorial array technology. (ii) Derive and characterize a population of clinically viable ESC-derived muscle progenitor cells using a dynamic, three-dimensional (3D), bioengineered niche. The tailored niche would be comprised of a multifunctional hydrogel that exhibits “excitation-contraction” dynamics. We will then functionalize this hydrogel with optimized ECM components and use it to investigate myogenic differentiation of ESCs in a 3D environment, and to derive engraftable muscle progenitor cells from ESCs. (iii) Investigate the therapeutic efficacy of ESC-derived progenitors for treating DMD pathology using animal models. The molecular pathways involved in myogenic differentiation of ESCs will be analyzed using proteomics and transcriptomics tools. Successful completion of this study could offer broad applicability of stem-cell-based therapies for treating all types of muscle wasting diseases and other pathologies associated with dysfunctional muscles. Unraveling the microenvironment factors and molecular events determining the commitment of ESCs into specific lineages will significantly increase our understanding of stem cell biology and their application in regenerative medicine. In addition, the multifunctional hydrogel (mechanical actuator) developed here could find many applications in the field of artificial functional implants where a muscle-like response is desirable, cardiac tissue repair, drug delivery, and biomimetic devices.
Statement of Benefit to California: 
The proposed study seeks to develop a clinically viable cell transplantation therapy based on pluripotent embryonic stem cells (ESCs) for treating muscular dystrophies (MDs), especially Duchenne muscular dystrophy (DMD). DMD is the most common form of MD that limits motility and shortens life expectancy of children, and is estimated to occur 1 in 3500 male births. DMD is characterized by progressive muscle wasting, limited ambulation, compromised lung or cardiac function, paralysis, and ultimately premature death. DMDfund (http://www.dmdfund.org), a California-based forum dedicated to families of children affected by DMD, emphasizes the devastating nature of this disease “... in contrast to cancer, DMD currently is uniformly fatal. As a result there is only a 3-fold difference in the number of childhood deaths due to cancer vs. DMD, but DMD research is relatively scarce. The paucity of research may be the reason that there is no cure for this devastating neuromuscular disease. Without research, there is no hope. Shouldn't all people at least been given the chance to hope?” Clearly, there is a need to develop new paradigms for treating DMD. The PI has proposed one possible approach to address this need and it will contribute to the State of California and its citizens in the many ways: Clinical benefits: Successful completion of the project will help develop new stem-cell-based therapies for treating DMD and other muscle wasting diseases. Unraveling the microenvironment factors and molecular events that determine the commitment of ESCs will significantly increase their treatment potential. Concepts and knowledge gained from the study can translate into other areas of regenerative medicine. Economic benefits: There are two ways the proposed work could contribute to the economy of California. First, improvements in DMD treatment could bring down the healthcare costs. Second, tools and technologies developed during the course of this study (soft mechanical actuators, smart biomimetic hydrogels, etc.) can find various other applications in biomedical fields such as artificial functional implants, cardiac tissue repair, drug delivery, and biomimetic devices. Such devices could be of great interest to California-based biotechnology companies. The PI’s past work involving musculoskeletal tissues has contributed to a start-up biotech company located in California, and the PI hopes to contribute similarly through the proposed studies. Education, training, and awareness: One of the most important components of the PI’s laboratory is training future leaders in the biomedical/stem cell field. We expect to train 10-12 researchers within the course of this project (clinical fellows, postdoctoral fellows, graduate students, undergraduate students, and high school students). These very students and trainees will, in the future, lead to the development of newer and more advanced strategies for regenerative medicine.
Progress Report: 
  • The overarching goal of this proposal is to develop robust clinically viable stem cell based therapeutics for muscle wasting focusing on Duchenne Muscular Dystrophy. Three specific aims were proposed to achieve this goal, and during the past year we have made significant progress towards this goal. The focus of aim one is to optimize the microenvironment factors comprising of cell-matrix interaction, cytokines, and cell-secreted morphogens on differentiation of stem cells into muscle cells. Stem cells require complex signals for differentiation and many of which are unknown, making it a challenge to direct tissue specific differentiation. We have adopted a stepwise differentiation strategy to promote myogenic differentiation of pluripotent stem cells (embryonic stem cells, ESCs and induced pluripotent stem cells, iPSCs). This involves differentiating the pluripotent stem cells into mesoderm progenitor cells followed by differentiating them into muscle cells. Our experimental findings show that our approach promotes efficient mesoderm differentiation of pluripotent stem cells. These extensively expandable ESC/iPSC-derived mesoderm progenitor cells are now being subjected to myogenic differentiation. We have also identified and optimized the combination of soluble factors that promote myogenic differentiation of muscle progenitor cells and stem cells. These soluble factors were found to promote myotube formation of muscle progenitor cells, in addition to promoting myogenic differentiation of stem cells. In an effort to understand the role of cell-matrix interactions, we have developed a novel method to decellularize the native skeletal muscle while maintaining their structural, biochemical composition, and mechanical properties unaltered. This approach has much more implications than supporting myogenic differentiation because it can be used as a model system to examine the changes ECM undergoes with pathological changes and how these changes affect stem cell myogenic differentiation and engraftment.
  • The second aim of the proposed study is to test the hypothesis that a bioengineered niche exhibiting “excitation-contraction” dynamics encoded with biochemical cues can be used as a 3D microenvironment to promote myogenic differentiation of stem cells. The first goal of this aim is to develop a bioengineered synthetic niche recapitulating the biophysical cues of native skeletal muscle. To this end, we have developed synthetic hydrogel based biocompatible electro-mechanical matrices, which not only provide three-dimensional structural support to the embedded cells but also can simultaneously provide dynamic mechanical and electrical cues to the cells. A unique aspect of these matrices is that they can undergo reversible, anisotropic bending dynamics in an electric field and functions like multi-functional mechanical actuators. The direction and magnitude of this bending can be tuned through the hydrogel crosslink density while maintaining the same electric potential gradient, allowing precise control over the mechanical strain imparted to the cells in a three-dimensional environment. Our results showed that these bioengineered electro-mechanical niches not only support stem cell culture but also promotes their proliferation and differentiation. The third aim of the proposed study is on evaluating the engraftment and differentiation of in vitro conditioned stem cells using animal models. Based on the progress made in aims 1 and 2, we are certain that we will be able to initiate the animal studies soon.
  • In sum, we have made significant progress in aims 1 and 2 of the proposed study. We have submitted one manuscript and three more manuscripts are under preparation. Another important achievement is training the researchers in stem cells. In addition to the postdoctoral and graduate fellows, we also trained undergraduate and high school students; Jomkuan Theprungsirikul from United World College, Montezuma, NM, had spent the summer in our lab to learn more about regenerative medicine and its potential in irradiating the public health problems. The PI visited Francis Parker School and gave a talk on stem cells on September 23 (Stem Cell Awareness Day). The PI also gave an invited talk on stem cell and regenerative medicine at the 3rd International Congress of NanoBiotechnology & Nanomedicine NanoBio 2009 held in San Francisco, CA.
  • N/A
  • During the reporting period, we successfully developed a protocol for deriving progenitor cells from human embryonic stem cells, which is being written up for a publication. The ESC-derived progenitor cells were found to undergo both myogenesis in vitro and in vivo. We were able to significantly expand these cells in vitro and the in vitro cultured cells expressed a number of muscle markers Pax3, Myf5, desmin, and MyoG. A muscle injury model was then used to investigate the in vivo viability and engraftment efficiency of these cells. A significant fraction of the transplanted cells were found to be engrafted. Additionally, we observed localization of a large number of transplanted cells in the centers of muscle fibers indicating the contribution of the transplanted cells towards the muscle regeneration. We have also developed a muscle-like synthetic material (termed as electromechanical material) that simultaneously provides mechanical and electrical cues to the embedded cells. A manuscript based on these results is published in Advanced Functional Materials, a highly regarded journal in interdisciplinary materials science. This work also received significant press coverage. The above-developed system will allow us determine the effect of various physicochemical cues of the matrix on myogenic commitment and maturation of progenitor cells.
  • During the reporting period, we successfully developed a protocol for deriving progenitor cells from human embryonic stem cells, which is being written up for a publication. The ESC-derived progenitor cells were found to undergo both myogenesis in vitro and in vivo. We were able to significantly expand these cells in vitro and the in vitro cultured cells expressed a number of muscle markers Pax3, Myf5, desmin, and MyoG. A muscle injury model was then used to investigate the in vivo viability and engraftment efficiency of these cells. A significant fraction of the transplanted cells were found to be engrafted. Additionally, we observed localization of a large number of transplanted cells in the centers of muscle fibers indicating the contribution of the transplanted cells towards the muscle regeneration. We have also developed a muscle-like synthetic material (termed as electromechanical material) that simultaneously provides mechanical and electrical cues to the embedded cells. A manuscript based on these results is published in Advanced Functional Materials, a highly regarded journal in interdisciplinary materials science. This work also received significant press coverage. The above-developed system will allow us determine the effect of various physicochemical cues of the matrix on myogenic commitment and maturation of progenitor cells.
  • We have developed a protocol devoid of genetic manipulations to derived progenitor cells with myogenic differentiation potential from human embryonic stem cells (hESCs). These hESC-derived cells underwent myogenic differentiation in vitro both in the presence and absence of serum in culture medium. When transplanted in vivo into an injured muscle, these pre-myogenically committed cells were viable in tibialis anterior muscles 14 days post-implantation. A manuscript describing these results have been published (Hwang Y, Suk S,Lin S, Tierney M, Du B, Seo T, Mitchell A, Sacco A, Varghese S. Directed in vitro myogenesis of human embryonic stem cells and their in vivo engraftment. PLoS One, 8, e72023 (2013). We have further modified the culture conditions to improve myogenic differentiation. When transplanted into injured muscles of immune-deficient NOD/SCID mice, a significant portion of fraction of the transplanted cells were found to be engrafted. Additionally, we observed localization of a large number of transplanted cells in the centers of muscle fibers indicating the contribution of the transplanted cells towards the muscle regeneration. Additionally, we also observed contribution of the transplanted donor cells towards the satellite compartment. The high proliferative capacity of hESCs along with their ability to differentiate into functional skeletal myogenic progenitor cells and engraft in vivo without teratoma formation highlights their potential therapeutic applications to ameliorate skeletal muscle defects and injuries.

Combination therapy to Enhance Antisense Mediated Exon Skipping for Duchenne Muscular Dystrophy

Funding Type: 
Early Translational from Disease Team Conversion
Grant Number: 
TRX-05426
ICOC Funds Committed: 
$0
Disease Focus: 
Muscular Dystrophy
Pediatrics
Stem Cell Use: 
Adult Stem Cell
oldStatus: 
Active
Public Abstract: 
Duchenne muscular dystrophy (DMD) affects 1 in every 3,500 boys worldwide. DMD is caused by mutations in the gene encoding dystrophin, a protein key to muscle health. DMD patients are typically weaker than normal by age 3, and with progressive muscle weakness most loose the ability to walk by age 11. DMD progresses to complete paralysis, respiratory insufficiency heart failure, and death, usually before the age of 25. No therapies exist that address the primary defect or dramatically alter the debilitating disease. Exon-skipping is an emerging therapy in which anti-sense oligonucleotide (AO) guided-RNA splicing rescues expression of a partially functional dystrophin; but it is unclear if efficacy will be optimal for clinical gain. We identified a combination therapy that improves the efficacy of exon-skipping in mouse muscle and human DMD patient-stem-cell-derived muscle cells. The DMD mouse model will be used to establish dosing and efficacy. To determine if combination therapy promotes exon skipping in human DMD patient cells with different DMD mutations, DMD patient derived stem cells converted into muscle-like cells in culture and screened for efficacy of combination drug relative to AO alone. The proposed research program will complete studies to identify a single drug/AO combination as a developmental candidate anticipated to treat up to 13% of DMD patients; although the strategy is likely generalizable to enable treatment of 70% of DMD patients.
Statement of Benefit to California: 
Duchenne muscular dystrophy (DMD) is a fatal genetic disorder, caused by a defect in the gene that produces dystrophin, a protein critical for normal skeletal muscle function. DMD affects more than 1,000 boys in California. Muscle weakness first appears in boys in the hips and legs and progressively extends to every muscle in the body such that most affected individuals require a wheelchair by age 11, have trouble feeding themselves by their late teens and ultimately loose most muscle function. Patients usually die by age 25 from respiratory or cardiac insufficiency. In addition to the human suffering, DMD places a large economic burden on patients, their families and society. Patients require intensive medical care because they cannot perform the simplest activities of daily living. Eventually, each individual requires ventilation and 24/7 care. The proposed combination therapy is predicted to cause skeletal muscle cells to skip DMD exon 51 and express a partially functional dystrophin protein, lessening the severity of DMD. A therapy that effectively slows or reverses disease will allow patients to lead longer, more productive lives and reduce costly supportive services—progress that will benefit patients, their families and society. Our proposal stands to specifically benefit Californians in another way: Because the University of California owns the intellectual property to the combined therapy, our success could ultimately lead to revenue for a state institution.
Progress Report: 
  • Duchenne muscular dystrophy (DMD) is the most common muscular dystrophies and the most common fatal genetic disorder of childhood. Approximately one in every 5,000 boys worldwide is affected with DMD often caused by spontaneous mutations. Extrapolating from population based studies, there are over 15,000 people currently living with DMD in the US alone. DMD is a devastating and incurable muscle-wasting disease caused by genetic mutations in the gene that codes for dystrophin, a protein that plays a key role in muscle cell health. Children with DMD are typically weaker than normal by age three, and progressive muscle weakness of the legs, pelvis, arms, neck and other areas result in most patients requiring full-time use of a wheelchair by age 11. Eventually, the disease progresses to complete paralysis and increasing difficulty in breathing due to respiratory muscle dysfunction and heart failure, with death usually occuring before the age of 25. While corticosteroids can slow disease progression and supportive care can extend lifespan and improve quality of life, no therapies exist that address the primary defect or dramatically alter the debilitating disease course.
  • Exon-skipping is a promising therapy that aims to repair the expression of the dystrophin protein by repairing the RNA. We have identified a combination therapy that improves the effectiveness of exon-skipping therapy in mouse muscle and in human DMD patient stem cell derived muscle cells in culture. In exon skipping the genetic defect is directly repaired inside of each muscle cell. Thus, this therapy is predicted to lessen the disease severity.
  • Early research on this combination therapy for Duchenne used human DMD patient stem cells including: reprogrammed patient fibroblasts converted into muscle-like cells in culture or when transplanted in mice. We have made a panel of these cells with different mutations to assess efficacy in a range of DMD mutations. These cells are necessary because each patient’s mutation in the dystrophin gene is different. In order to know who will or will not benefit from the exon-skipping therapy, individualized cell culture and mouse transplant models from a number of DMD patients must be created to effectively characterize the combination therapy. At 12 months of the CIRM-funded research program, we have established optimal oral dosing of dantrolene that is compatible with 6 month long-term testing in dystrophic mice and optimal dosing of morpholino antisense oligo. The combination therapy is well tolerated by mice, and dystrophin rescue is increased in short term experiments. 6 month treatment experiments are being initiated that will test if the induction of dystrophin can reduce the severity of the disease in the dystrophic mice. Since exon-skipping therapy relies on knowing individual patients exact DNA mutation, this is a form of personalized genetic medicine. While the specific combination therapy being developed here will treat up to 13% of DMD patients, the strategy is likely to be generalized to be able to treat up to 70% of DMD patients.

Engineered iPSC for therapy of limb girdle muscular dystrophy type 2B

Funding Type: 
Early Translational IV
Grant Number: 
TR4-06711
ICOC Funds Committed: 
$1 876 253
Disease Focus: 
Muscular Dystrophy
Pediatrics
Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 
Limb girdle muscular dystrophy type 2B (LGMD 2B) is a form of muscular dystrophy that leads to muscle degeneration and disability. In LGMD 2B, a vital muscle protein is mutated, and its absence leads to progressive degeneration of muscles in the body that are needed for mobility. To create a therapy, we will provide a new supply of stem cells that carry the missing protein that is lacking. These cells will be delivered to the body in such a way that they will engraft into the muscles and produce new, healthy muscle tissue on an ongoing basis. We now possess methods to create stem cells that can become muscle cells out of adult skin cells by a process known as “reprogramming”. By reprogramming adult cells, together with addition to them of a correct copy of the gene that is mutated in LGMD 2B, we will create stem cells that have the ability to create new, healthy muscle cells in the body of a patient. This is the type of strategy that we are developing in this proposal. The corrected muscle stem cells will be transplanted into mice with LGMD 2B, and the ability of the cells to generate healthy new muscle tissue and increased muscle strength will be evaluated. This project could lead to a new stem cell therapy that could improve the clinical condition of LGMD 2B patients. If we are successful with this disease, similar methods could be used to treat other degenerative disorders, and perhaps even some of the degeneration that occurs during muscle injury and normal aging.
Statement of Benefit to California: 
The proposed research could lead to a stem cell therapy for limb girdle muscular dystrophy type 2B (LGMD 2B). This outcome would deliver a variety of benefits to the state of California. There would be a profound personal benefit to the Californians affected directly or indirectly by LGMD 2B. Progress toward a cure for LGMD 2B is also likely to accelerate the development of treatments for other degenerative disorders. The most obvious targets would be other forms of muscular dystrophy and neuromuscular disorders. Muscle injury, and even some of the normal processes of muscle aging, may be treatable by a similar strategy. An effective stem cell therapy for LGMD 2B would also bring economic benefits to the state by reducing the huge burden of costs associated with the care of patients with long-term degenerative disorders. Many of these patients would be more able to contribute to the workforce and pay taxes. Another benefit is the effect of novel, cutting-edge technologies developed in California on the business economy of the state. Such technologies can have a profound effect on the competitiveness of California through the formation of new manufacturing and health care delivery facilities that would employ California citizens and bring new sources of revenue to the state. Therefore, this project has the potential to bring health and economic benefits to California that are highly desirable for the state.

Combination therapy to Enhance Antisense Mediated Exon Skipping for Duchenne Muscular Dystrophy

Funding Type: 
Disease Team Therapy Planning I
Grant Number: 
DR2-05426
ICOC Funds Committed: 
$86 414
Disease Focus: 
Muscular Dystrophy
oldStatus: 
Closed
Public Abstract: 
A drug was identified through the use of muscle stem cells that can enhance the effectiveness of exon skipping by antisense oligonucleotides to the DMD gene to restore dystrophin expression and at least partially correct the defect responsible for loss of muscle function in Duchenne. We propose to test the effectiveness of this drug in combination with antisense oligonucleotides as a novel therapeutic strategy for Duchenne muscular dystrophy (DMD). DMD is the most common muscular dystrophy and leads to progressive muscle loss in boys resulting in severe weakness, and is caused by mutations in the DMD gene. DMD generally leads to death in the teens or early 20’s, making Duchenne one of the most severe disorders in humans. Further, Duchenne occurs in 1/3500 boys, making it one of the most common genetic disorders. There are no highly effective therapies. Thus, there is an urgent need to develop new and highly effective therapies. We propose to perform the necessary studies using DMD patient-derived iPS and animal models to perform safety studies that will permit regulatory approval to test the safety and efficacy of the combination therapy in Duchenne muscular dystrophy. The goal of the treatment is to make a functional dystrophin protein the patient’s body by altering the RNA in each muscle cell. Preliminary results indicate that the process is relevant to about 70% of those afflicted by Duchenne.
Statement of Benefit to California: 
Since Duchenne muscular dystrophy is the most common lethal genetic disorder, there are over 1,000 patients affected in the state of California alone, 15,000 nationwide, and 300,000 worldwide. Duchenne muscular dystrophy has a large direct economic impact with intensive medical care with substantial disability. There is an obvious huge impact on the family as well. More effective therapies will directly benefit these families, lead to increased productivity. Further, a California based company will have developed a key therapy for an otherwise lethal genetic disorder further demonstrating California’s leadership in medical science, and generating novel business opportunities within the Biotechnology industry in California.
Progress Report: 
  • Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy and one of the most common fatal genetic disorders. Approximately one in every 3,500 boys worldwide is affected with DMD. Extrapolating from population based studies, there are over 15,000 people currently living with DMD in the US. DMD is a devastating and incurable muscle-wasting disease caused by genetic mutations in the gene that codes for dystrophin, a protein that plays a key role in muscle cell health. Children are typically weaker than typical by age three, and progressive muscle weakness of the legs, pelvis, arms, neck and other areas result in most patients requiring full-time use of a wheelchair by age 11. Eventually, the disease progresses to complete paralysis and increasing difficulty in breathing due to respiratory muscle dysfunction and heart failure. The condition is terminal, and death usually occurs before the age of 25. While corticosteroids can slow disease progression and supportive care can extend lifespan and improve quality of life, no therapies exist that address the primary defect or dramatically alter the debilitating disease course.
  • The Planning Award funded the organization of the scientific and clinical team to apply for a well-defined CIRM Disease Team Therapy Development Award. The PI and project manager travelled to San Francisco to a CIRM sponsored workshop to gain training and insight in developing a Target Product Profile, to meet with other CIRM disease team grantees and aid in developing the most effective grant application. During that trip, we also met with investigators at the California based CRO, SRI, toured the SRI facilities, and planned for the assembly of the team that would us develop appropriate toxicology package for the proposed drug development. Several face-to-face meetings and conference calls with leaders in Duchenne advocacy, DMD clinic directors and industry partners were orchestrated to assess enthusiasm for the proposed project, which was across the board very high. A day long planning grant meeting was held on Dec 9th, 2011 in Santa Monica with participation of over 30 national and local academic, CRO, and industry experts in exon skipping, Duchenne Muscular Dystrophy, clinical trials planning, FDA regulatory practices and drug development. We identified and secured a leading industry partner necessary for streamlining the proposed work. Following the meeting, a series of weekly/daily conference calls between team members from UCLA, SRI and the industry partner enabled us to develop details of the proposal. During the planning grant period we were awarded a provisional patent for the combination therapeutic that is being moved forward in this proposal. Through discussions with leaders in the clinical care of Duchenne Muscular Dystrophy, leaders in antisense mediated exon skipping, and leaders in pre-IND drug development, we built a strong team to propose all IND enabling work to bring a proposed combination therapy for exon skipping as a novel Duchenne muscular dystrophy therapy.
  • Exon-skipping is a promising therapy that aims to repair the expression of the dystrophin protein by altering the RNA, but it is unclear whether it will be effective enough to lead to clinical improvements. We have identified a combination therapy that improves the effectiveness of exon-skipping therapy in mouse muscle and in human DMD patient stem cell derived muscle cells in culture. Because the genetic defect is being directly repaired inside of each muscle cell, this therapy is predicted to lessen the disease severity. The early research and further development of the proposed combination therapy require screening for drug efficacy and toxicity using human DMD patient stem cells including: reprogrammed patient fibroblasts converted into muscle-like cells in culture or when transplanted in mice. These cells are necessary because each patient’s mutation in the dystrophin gene is different. In order to know who will or will not benefit from the exon-skipping therapy, individualized cell culture and mouse transplant models from a number of DMD patients must be created to effectively characterize the combination therapy. The proposed research program will complete necessary efficacy and toxicity studies to allow submission of appropriate material to the FDA to allow testing of this novel combined therapeutic in children with DMD. It will also involve a team of clinical trialists who will incorporate findings in planning optimal trial design and ensure clinical trial readiness by the grants end. Since exon-skipping therapy relies on knowing individual patients exact DNA mutation, this is a form of personalized genetic medicine. While the specific combination therapy being developed here will treat up to 13% of DMD patients, the strategy is likely to be generalized to be able to treat up to 70% of DMD patients.

Pages

Subscribe to RSS - Muscular Dystrophy

© 2013 California Institute for Regenerative Medicine