TONIGHT TRUMP SUPPORTS Gene Therapy for Pompe Disease
TONIGHT PRESIDENT TRUMP* INTRODUCED THE NATION TO MEGAN CROWLEY SHE HAS POMPE DISEASE. AND HOW DO YOU THINK YOU CAN CURE POMPE DISEASE
STEM CELLS are involved with MEGAN !!!
Tonight, when President Donald Trump speaks at his First Address to a Joint Session of Congress, there will be a special guest sitting with First Lady Melania Trump – Megan Crowley.
Megan is a 20-year-old sophomore student at University of Notre Dame who was diagnosed with Pompe disease when she was 15 months old. She blogs about her extraordinary life at highheeledwheels.com/
Megan is the daughter of John Crowley, CEO of Amicus Therapeutics. His struggle to find a treatment for Pompe disease was the basis for the Harrison Ford film Extraordinary Measures.
It is hopeful that Megan’s presence tonight will ease many rare disease patients' concerns about how President Trump will change the way chronic, rare, and/or pre-existing conditions are managed and researched. With taht said, it is not clear what the current administration’s philosophy is towards the rare disease community other than to note that the healthcare system ‘is a mess’.
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Research published in Molecular Therapy by a team of investigators from Japan suggests that the exploration of lentiviral gene transfer as a complimentary therapeutic modality may be key to unlocking a new era of Pompe disease-related breakthroughs.1
Sato et al. generated late-onset Pompe disease-specific induced pluripotent stem cells (iPSC) (derived from a late-onset Pompe disease patient) and differentiated them into cardiomyocytes. The differentiated cardiomyocytes demonstrated clear markers of Pompe disease (e.g., glycogen accumulation and lysosomal enlargement). Subsequently, study authors discovered that lentiviral gene replacement therapy mitigated the cardiomyocyte-related Pompe manifestations in a statistically significant manner.1
Lentiviral technology is a cutting-edge form of gene therapy in which a transplanted repair gene is introduced into the cell as a `passenger’ transported by a virus which has been stripped of its ability to replicate but - owing to its infective properties and unique ability to penetrate both dividing and non-dividing cells - represents 1 of the most efficient methods of gene delivery currently available.2
Pompe Disease Pathophysiology
Pompe disease is a hereditary lysosomal storage disorder which impacts approximately 1 out of every 40,000 live births. The etiology of this rare, usually-fatal form of muscular dystrophy is rooted in roughly 300 distinct genetic mutations in the acid alpha-glucosidase (GAA) gene, which expresses an enzyme of the same name. The GAA enzyme is an essential facilitator of the glycogen metabolic process. Glycogen is a stored form of sugar. Via interaction with the GAA enzyme in the lysosome, glycogen is converted into glucose. The body uses glucose to fuel muscles. Lysosomes are cytoplasmic organelles which serve as intracellular `waste management centers,’ eliminating debris and breaking down multiple substances into manageable components that are subsequently utilized or disposed of via other cellular processes.3
In the case of Pompe disease, the GAA enzyme is either nonexistent or underrepresented. When this critical protein is missing, lysosomal glycogen builds up throughout the body, resulting, in a spectrum of debilitations which generally culminates in loss of life.3
Age-of-onset ranges widely. Severity is also variable and dependent on degree of GAA enzyme deficiency. Early-onset Pompe is characterized by complete or near complete GAA enzyme deficiency. The typical early-onset Pompe disease patient will die due to severe cardiac muscle deterioration before his or her first birthday. Late-onset Pompe disease, a partial GAA deficiency, generally manifests between the ages of 10 and 60. Late-onset Pompe is also deadly (following a longer period of disease progression of up to several years, during which progressive muscle weakness begins to inhibit respiration, culminating in eventual mortality as a result of respiratory failure).3
Toward A New Pompe Therapy Paradigm?
Since 2006, when the first enzyme replacement therapy (ERT) - alglucosidase alfa - gained US Food and Drug Administration (FDA) approval for early-onset Pompe (approval for an almost biologically identical form of alglucosidase alfa for late-onset Pompe followed in 2010), ERT has represented the-state-of-the-art of Pompe disease treatment. There is no cure for Pompe disease but ERT has been demonstrated to increase skeletal muscle strength, walking distance, respiratory function and survival rates.3
The aforementioned clinical responses, however, are markedly variable. In addition, many Pompe patients become resistant to ERT therapy as a result of neutralizing antibody formation and autophagic buildup. For such cases, “There are few available treatment modalities at this point and novel therapeutic strategy is warranted,” asserted Sato and colleagues. The Japanese research team presented data which positioned lentiviral gene therapy as a potential alternative treatment modality to supplement ERT and other standard clinical interventions.1
Investigators evaluated 3 iPSC clones from 1 late-onset Pompe disease patient and 1 clone from 1 healthy control subject. Several pluripotency markers were assessed via reverse transcription polymerase chain reaction. Both Pompe disease and control iPSC were shown to have similar characteristics; in both, almost all of the analyzed pluripotency markers were expressed equally. Pluripotency is defined as the ability of individual cells to initiate all lineages of the mature human organism. A pluripotent cell is, in essence, a blank slate. Pluripotent stem cells can become any type of tissue in the body, with the exception of placental tissue.4
Genetic analysis of Pompe disease iPSC demonstrated compound heterozygote mutations which corresponded to late-onset Pompe disease. Electron microscopy was employed to compare glycogen accumulation in the lysosomes of Pompe disease iPSC with control. Pompe disease iPSC were shown to have weak GAA enzyme expression and increased glycogen content compared to control iPSC. Citing the aforementioned evidence, investigators concluded that “Pompe disease iPSC have disease-specific characteristics both pathologically and biochemically.”
