BARCELONA DOG "CURE"

[maxies-mom]

Hi Gang
I have read the Barcelona papers published 1st Feb (please see citation below) and have passed them along to our Endo for comment.
While the general feeling in the Endo community is that this is hopeful, there is only one hurdle to overcome and that is the autoimmune reaction in humans with T1.

From what I can understand of the Barcelona Project, gene manipulation allows muscle to produce Ins and Gck. From the paper;

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.

Clearly a long ways to go yet but this is the part that absolutely grabbed my attention...

The proposed clinical trial in diabetic pet dogs will greatly help defining the safety and
efficacy profile of our approach in humans

Fatima Bosch and her team have my undivided attention. If they can prove the concept in naturally occurring T1 where an autoimmune response is present, this may well be the little light shining that sparks to a flame.

Much love
Philly

Treatment of Diabetes and Long-term Survival Following Insulin and Glucokinase Gene Therapy
David Callejas1,2,5*, Christopher J. Mann1,2,5*, Eduard Ayuso1,2,5, Ricardo Lage1,2,5, Iris
Grifoll1,2,5, Carles Roca1,2,5, Anna Andaluz3, Rafael Ruiz-de Gopegui3, Joel Montané1,2,
Sergio Muñoz1,2,5, Tura Ferre1,2,5, Virginia Haurigot1,2,5, Shangzhen Zhou6, Jesús
Ruberte1,4,5, Federico Mingozzi6,, Katherine A. High6,7, Felix Garcia3, and Fatima
Bosch1,2,5#
1Center of Animal Biotechnology and Gene Therapy, Departments of 2Biochemistry and
Molecular Biology, 3Animal Medicine and Surgery and 4Animal Health and Anatomy,
School of Veterinary Medicine, Universitat Autònoma Barcelona, Bellaterra, 5CIBER de
Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain, 6Division of
Hematology, Children’s Hospital of Philadelphia and 7Howard Hughes Medical Institute,
Philadelphia, USA.

 

[phoenix]

Fatima Bosch and her team have my undivided attention. If they can prove the concept in naturally occurring T1 where an autoimmune response is present, this may well be the little light shining that sparks to a flame.

Yes, totally agree, this is the first piece of research that I've thought ...maybe ....but the problem is one has to be an expert to really assess it .
I know GCK (Glucokinase) works as the glucose sensor for the beta cell. MODY 2 is due to a mutation in this GCK gene. I don't know if this applies in T1 where the beta cells are supposedly destroyed. (but what exactly does that mean?)


TBH, I'm not totally convinced that all T1s have the same condition ie we know that there are various antibodies found but we also know that there are some T1s ( as in ketosis prone and c peptide absent/almost absent) who have no evidence of antibody attack. A lot of people may have never actually been tested. If so then what 'cures' one may not work on another.

Will be interested in your endos comments.

 

[maxies-mom]

My son has Type 1B which apparently is the lack of any antibody activity and i concur, i think there are many variants, many triggers. What is exciting about this research and discovery is that they believe that the muscular genesis of Gck and Ins, the muscle itself may dodge any further autoimmune detection... time will tell.... which means whatever the cause of T1, there is a solution.
This and the Aussie trial vaccine are real beacons of hope.

Much love
Philly