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Type 1 cured in large dogs...

Discussion in 'Parents of Children with Type 1' started by Heather(CA), Feb 11, 2013.

  1. Heather(CA)

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    I know, it's not humans...But, much closer than mice. Hope.

    After a few shots, one time. The Type 1 has not come back for 4 years. No highs, no lows, not even after exercise. Shoot, I would be happy with those results for 1 year at a time...



    http://www.sciencedaily.com/releases/2013/02/130207114422.htm
     
    Last edited: Feb 11, 2013
  2. Sarah Maddie's Mom

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  3. joy orz

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    Wow Heather, that is fantastic news.

    Considering all the research Banting did on dogs and insulin, this seems like a great big step!
     
  4. Christopher

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  5. ChristineJ

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    Interesting! MODY 2 involves a deficiency in the enzyme Glucokinase, which is one of the factors in this study. I wonder what the implications will be, if any, toward a cure for MODY 2?

    Christine
     
  6. Bigbluefrog

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    Hope. Positive steps towards a cure
     
  7. Heather(CA)

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    Yes, my thoughts exactly :)
     
  8. sooz

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    Thank you for posting this Heather. Hope has become my middle name...
     
  9. SarahKelly

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    I read this the other night online and both my husband and I felt completely encouraged by it. He felt that even if you'd need to have one shot a day to maintain even BG he'd do it. I love hearing news tidbits that get him filled with hope because after all he's heard in over 20yrs sometimes he doesn't get as hopeful.
    Thanks for sharing :)
     
  10. Darryl

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    A few excerpts from the full article:

    ABSTRACT

    We previously demonstrated that it is possible to generate a glucose sensor in skeletal muscle through co-expression of glucokinase (Gck) and insulin (Ins), increasing glucose uptake and correcting hyperglycemia in diabetic mice. Here, we demonstrate long-term efficacy of this approach in a large animal model of diabetes. A one-time intramuscular administration of adenoassociated viral vectors of serotype 1 (AAV1) encoding for Gck and Ins in diabetic dogs resulted in normalization of fasting glycemia, accelerated disposal of glucose after oral challenge, and no episodes of hypoglycemia during exercise for >4 years after gene transfer. This was associated with recovery of body weight, reduced glycosylated plasma proteins levels, and long-term survival without secondary complications. Conversely, exogenous insulin or gene transfer for Ins or Gck alone failed to achieve complete correction of diabetes, indicating that the synergistic action of Ins and Gck are needed for full therapeutic effect. This study provides the first proof-of-concept in a large animal model for a gene transfer approach to treat diabetes.

    INTRODUCTION

    Genetic engineering of skeletal muscle to counteract hyperglycemia is an attractive strategy to correct diabetes. Skeletal muscle is responsible for the disposal of ~70% of circulating glucose after a meal. In muscle, glucose utilization is controlled by insulinstimulated glucose transport through the glucose transporter type 4 (GLUT4) (5) and phosphorylation by hexokinase II (HKII), which has a low Km for glucose and is inhibited by glucose-6-phosphate, limiting glucose uptake (6). In diabetic muscle, due to the lack of insulin, GLUT4 translocation to the plasma membrane and HKII activity both decrease. In contrast to HKII, the liver enzyme glucokinase (Gck) has a high Km for glucose, is not inhibited by glucose-6-phosphate, and shows kinetic cooperativity with glucose (7). When expressed in skeletal muscle of transgenic mice, Gck facilitates glucose uptake only when blood glucose is high (8). However, during diabetes, constant basal levels of insulin are required to ensure the presence of GLUT4 on the cell membrane (5).
    Here, we used dogs treated with β-cell cytotoxic drugs as model of experimental diabetes (15), since large animal models of autoimmune diabetes are not available. We demonstrate that after a single intramuscular injection of AAV1 vectors, Ins and Gck transgenes act synergistically to achieve tight control of glycemia. This represents the first proof-of-concept study of long-term correction of diabetes in a large animal model using gene transfer.

    DISCUSSION

    Since the 1922 breakthrough discovery of Banting and Best, who corrected hyperglycemia in dogs using pancreatic extracts, exogenous insulin administration has been the mainstay of diabetes therapy. Alternative therapies have been studied, but thus far only a handful of approaches, mainly involving allo- or xeno-transplantation of pancreatic islets, have reached clinical application (2). In the clinical translation of bench results, the scale up to a large animal model represents perhaps one of the most critical steps. This was nicely demonstrated by the work done in gene transfer for hemophilia B (12,25-27) and Leber?s Congenital Amaurosis (13,28), where results in dogs were fully predictive of the outcome in humans.

    Our novel approach to control hyperglycemia, through genetic engineering of a ?glucose sensor? in skeletal muscle using AAV vectors, has permitted long-term, clinically meaningful regulation of glycemia in a large animal model of diabetes.
    Our approach circumvents a number of the challenges of diabetes therapy. In contrast to allotransplantation where supplies of human pancreatic islets are limiting, AAV vector manufacturing is robust and unlimited. Moreover, longterm (>10 years) transgene expression has been documented in humans following AAV vector administration to skeletal muscle (30).

    Long-term follow-up of treated dogs suggests that muscle expression of Ins and Gck is well tolerated over a prolonged period. Studies confirmed the safety of the approach even under marked physical exertion, when high levels of glucose consumption increase the risk of hypoglycemic episodes. The use of a large animal model with a long lifespan allowed us to follow animals for early indicators of secondary complications. The absence of clinical findings such as cataracts or urinary tract infection, and the reduction of biomarkers such as glycosylated proteins (fructosamine), suggest that Ins and Gck gene transfer may prevent diabetes complications. Hence, normalization of glycemia with a onetime intervention could result in a substantial improvement in patients? quality of life, particularly in populations with difficulties in diabetes management, such as brittle diabetes (35).

    One possible limitation of the results presented here is that the dog model of diabetes used in this study does not fully mimic the immunological state of type 1 diabetic patients. However, while future studies in autoimmune models of diabetes are warranted, studies in mice (36), dogs (37), and humans (38) would suggest that targeting muscle with AAV vectors may at least partially escape immune recognition. This may be the result of lower levels of MHC class I presentation in this tissue, or the result of the induction of apoptosis of reactive T cells (36,38). In summary, our data represent the first demonstration of long-term correction of diabetes in a large animal model using gene transfer.

    Future safety and efficacy studies will help to determine the range of Ins and Gck vector doses that are therapeutic, as well as the Gck/Ins expression ratio that is optimal for a tight control of glycemia. These studies will provide the bases for the initiation of a clinical veterinary study in companion animals with diabetes, a strategy also proposed for the clinical development of cancer therapeutics (39). The proposed clinical trial in diabetic pet dogs will greatly help defining the safety and efficacy profile of our approach in humans. One added advantage of this strategy is also related to the fact that large experimental animal models of autoimmune diabetes do not exist, thus companion animals with naturally occurring diabetes constitute an extremely valuable and stringent model. In conclusion, this study lays the foundation for the clinical translation of this approach to veterinary medicine, and possibly to humans.
     
  11. mmgirls

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    Ok so do I understand THIS, It is not a correction of autoimmunity, but a treatment to skeletal muscle that deals with the excess glucose due to no insulin production? It allows the muscle act as a correction device, the muscle uses up the excess glucose but does not overuse glucose to have a hypo?

    This is so inovative, it is a wonder that someone thought of this.

    I am happy for this step forward, even if it is not a step froward that will benifit humans, it get people thinking.
     
  12. Megnyc

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    If I am understanding this correctly the dogs had 2 genes injected into their muscles (in viruses). One makes insulin and the other tells the muscles how much glucose to absorb. Therefore, it is completely bypassing the pancreas and the need to regenerate beta cells. So, this could conceivably also help those of us who have diabetes as a result of the loss of their pancreas. I could be missing something here but this seems really promising.
     
  13. mmgirls

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    Yes that is how I read it, bypassing the Pank by all means. Not sure if it would also be a treatment for T2 or other forms of D were significant resistance has to be overcome.
     
  14. kim5798

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    Hope is hope. love it.
     
  15. mmgirls

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    Yes, any step that gives us us a clearer picture is a benifit.

    Even if it is for our 4 legged freinds, FOR NOW.
     
  16. momtojess

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    This is nice to see a different direction in research, but I don't understand.

    I understand the idea of an enzyme that regulates the uptake of glucose from the blood stream, but I don't understand where exactly insulin will come from (as needed for basal). It says it will express an insulin gene but I don't understand that exactly, is it a man-made gene that will make insulin?
     

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