Skip to main content
  • More from ADA
    • Diabetes Care
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care in Diabetes
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care
  • Subscribe
  • Log in
  • My Cart
  • Follow ada on Twitter
  • RSS
  • Visit ada on Facebook
Diabetes

Advanced Search

Main menu

  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • ADA Scientific Sessions Abstracts
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • ADA Scientific Sessions Abstracts
    • Diabetes COVID-19 Article Collection
    • Diabetes Symposium 2020
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Submit Cover Art
    • ADA Journal Policies
    • Instructions for Authors
    • ADA Peer Review
  • More from ADA
    • Diabetes Care
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care in Diabetes
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care

User menu

  • Subscribe
  • Log in
  • My Cart

Search

  • Advanced search
Diabetes
  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • ADA Scientific Sessions Abstracts
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • ADA Scientific Sessions Abstracts
    • Diabetes COVID-19 Article Collection
    • Diabetes Symposium 2020
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Submit Cover Art
    • ADA Journal Policies
    • Instructions for Authors
    • ADA Peer Review
Commentary

Gene Therapy for Type 1 Diabetes Moves a Step Closer to Reality

  1. Timothy O’Brien⇑
  1. Regenerative Medicine Institute and Department of Medicine, National Centre for Biomedical Engineering Science, National University of Ireland and Galway University Hospital, Galway, Ireland
  1. Corresponding author: Timothy O’Brien, timothy.obrien{at}nuigalway.ie.
Diabetes 2013 May; 62(5): 1396-1397. https://doi.org/10.2337/db13-0348
PreviousNext
  • Article
  • Figures & Tables
  • Info & Metrics
  • PDF
Loading

The prevalence of diabetes mellitus (DM) is assuming pandemic proportions and is currently estimated at 285 million cases (1). Although most cases are due to obesity-associated type 2 DM, there is also an increase in the annual prevalence of type 1 DM (2). It is estimated that 10% of the diabetic population have type 1 DM. Both forms of DM are associated with a long-term risk of microvascular and macrovascular complications (3) and the immediate risk of hypoglycemia.

There is abundant evidence that attainment of near normoglycemia will reduce the risk of complications associated with DM (4). However, attainment of near normoglycemia in patients with type 1 DM is limited by the occurrence of hypoglycemia. Patients with hypoglycemic unawareness are particularly prone to this problem as a limiting factor for achieving the required glycemic control. DM clinics globally have many patients with type 1 DM in whom recurrent hypoglycemia and the phenomenon of hypoglycemic unawareness present major clinical problems. Fortunately, there are many promising and exciting advances on the horizon for patients with this problem, including gene therapy as reported in this issue of Diabetes by Bosch and colleagues (5).

In the current study, the authors use an adeno-associated viral (AAV) vector to overexpress the genes for insulin and glucokinase in skeletal muscle in a canine model of DM. The study addresses the question of whether this gene therapy approach will result in long-term benefits in terms of attainment of near normoglycemia and avoidance of hypoglycemia. The approach was successful on both fronts. The authors demonstrate for the first time in a large animal model that this gene therapy approach has a beneficial therapeutic effect for up to 4 years. This is a major advance in the field of gene therapy for DM. Although gene therapy has promised much, progress has been slow largely because of issues with vector-related shortcomings. In this article, the authors use an AAV vector that results in long-lived transgene expression. Indeed, as the authors point out, AAV-mediated transgene expression has been detected 10 years after intramuscular delivery in humans (6). The use of AAV is certainly appropriate given the safety profile and the ability to obtain long-term gene expression (7). This vector has also had successful application in humans in other conditions requiring skeletal muscle expression such as hemophilia (8). In addition, success has been reported with this vector in clinical studies of Leber congenital amaurosis (9). Interestingly, the combination of insulin and glucokinase was necessary to have the beneficial effect while either gene alone was ineffective. The absence of hypoglycemia over 4 years is a particularly gratifying outcome.

The authors’ strategy in this article to engineer skeletal muscle is intriguing. Glucokinase was chosen because of its high Km for glucose and lack of inhibition by glucose-6-phosphate. Of key importance is the fact that glucokinase only stimulates glucose uptake by skeletal muscle when glucose levels are high, thus providing protection against hypoglycemia. However, as the GLUT 4 transporter is reduced in the absence of insulin, low level expression of basal insulin is also necessary. Thus, overexpression of two genes is required, which will certainly increase the complexity of the regulatory process to translate this therapy. This may be a substantial barrier to ultimate clinical application in humans and will need to be considered in the context of competing technologies. In terms of translational progress however, the work by this group progressing from murine to canine models paves the way for a clinical trial for the treatment of type 1 DM in veterinary practice. Another safety issue which will need consideration is the risk of hypoglycemia resulting from basal expression of insulin, which is required for GLUT 4 transporter expression in the cell membrane. While the current study did not demonstrate any hypoglycemic episodes this will need careful monitoring in future studies as the long lived expression of insulin will not be reversible.

Although the results reported in this study are of major significance in progressing the translational research agenda for gene therapy and DM, it should be borne in mind that there are other approaches to develop innovative therapies for type 1 DM (Fig. 1). While limitation of donor organs is a barrier to islet cell transplantation (10), xenotransplantation strategies are under development (11). β-Cell replacement strategies using embryonic stem cells, induced pluripotent stem cells, and adult stem cells hold promise (12,13). There are a number of recent publications suggesting that adult mesenchymal stem cells may have a glucose-lowering effect and therapeutic potential in the treatment of type 1 DM (14). Recent immunotherapy trials have not reported success, but the approach still holds promise (15). Finally, development of medical device technology holds great promise, and the use of continuous glucose monitoring, continuous subcutaneous insulin infusion, sensor-augmented pump therapy, and low glucose suspend technology are already resulting in improvements in clinical care for patients with type 1 DM (16–19). A recent article in this journal on a fully integrated artificial pancreas in type 1 DM demonstrates progress toward the development of a closed-loop system for the attainment of near normoglycemia (20). Thus as any new technology, such as gene therapy, is developed competing technologies should be considered, and ultimately the optimal approach to enhance patient care will be discovered.

FIG. 1.
  • Download figure
  • Open in new tab
  • Download powerpoint
FIG. 1.

Innovative therapies for DM. CSII, continuous subcutaneous insulin infusion; LGS, low glucose suspend.

Overall, the report by Bosch and colleagues is a substantial advance in the attempts to develop clinical gene therapy for type 1 DM. However, though there are substantial challenges on this translational pathway, they are worthy of pursuit given the ultimate prize if the approach is successful. The next step may involve a clinical trial in companion dogs, but ultimately human translation to a phase 1 dose escalation study will require toxicology studies performed under good laboratory practice conditions and further determination of optimal dose of both vectors. If safety is demonstrated, phase 2 and 3 studies will be required, which will demand considerable resources and cost. Although this study paves the way for a veterinary study, the pathway for human translation is still tortuous and over time will be evaluated in the context of competing technologies.

ACKNOWLEDGMENTS

The work of T.O. is supported by Science Foundation Ireland (SFI), Strategic Research Cluster (SRC), grant SFI: 09/SRC B1794; the European Regional Development Fund, FP7-HEALTH-2012-INNOVATION-1 grant 305736 (REDDSTAR, Repair of Diabetic Damage by Stromal Cell Administration); and research grants from Medtronic. T.O. is a founder, director, and equity holder in Orbsen Therapeutics. No other potential conflicts of interest relevant to this article were reported.

Footnotes

  • See accompanying original article, p. 1718.

  • © 2013 by the American Diabetes Association.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

REFERENCES

  1. ↵
    1. Shaw JE,
    2. Sicree RA,
    3. Zimmet PZ
    . Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract 2010;87:4–14pmid:19896746
    OpenUrlCrossRefPubMedWeb of Science
  2. ↵
    1. DIAMOND Project Group
    . Incidence and trends of childhood Type 1 diabetes worldwide 1990-1999. Diabet Med 2006;23:857–866pmid:16911623
    OpenUrlCrossRefPubMedWeb of Science
  3. ↵
    1. Rask-Madsen C,
    2. King GL
    . Vascular complications of diabetes: mechanisms of injury and protective factors. Cell Metab 2013;17:20–33pmid:23312281
    OpenUrlCrossRefPubMedWeb of Science
  4. ↵
    1. The Diabetes Control and Complications Trial Research Group
    . The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977–986pmid:8366922
    OpenUrlCrossRefPubMedWeb of Science
  5. ↵
    1. Callejas D,
    2. Mann CJ,
    3. Ayuso E,
    4. et al
    . Treatment of diabetes and long-term survival after insulin and glucokinase gene therapy. Diabetes 2013;62:1718–1729pmid:23378612
    OpenUrlAbstract/FREE Full Text
  6. ↵
    1. Buchlis G,
    2. Podsakoff GM,
    3. Radu A,
    4. et al
    . Factor IX expression in skeletal muscle of a severe hemophilia B patient 10 years after AAV-mediated gene transfer. Blood 2012;119:3038–3041pmid:22271447
    OpenUrlAbstract/FREE Full Text
  7. ↵
    1. Mingozzi F,
    2. High KA
    . Therapeutic in vivo gene transfer for genetic disease using AAV: progress and challenges. Nat Rev Genet 2011;12:341–355pmid:21499295
    OpenUrlCrossRefPubMed
  8. ↵
    1. Nathwani AC,
    2. Tuddenham EG,
    3. Rangarajan S,
    4. et al
    . Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med 2011;365:2357–2365pmid:22149959
    OpenUrlCrossRefPubMedWeb of Science
  9. ↵
    1. Maguire AM,
    2. High KA,
    3. Auricchio A,
    4. et al
    . Age-dependent effects of RPE65 gene therapy for Leber’s congenital amaurosis: a phase 1 dose-escalation trial. Lancet 2009;374:1597–1605pmid:19854499
    OpenUrlCrossRefPubMedWeb of Science
  10. ↵
    McCall M, Shapiro AM. Update on islet transplantation. Cold Spring Harb Perspect Med 2012; 2:a007823
  11. ↵
    1. van der Windt DJ,
    2. Bottino R,
    3. Kumar G,
    4. et al
    . Clinical islet xenotransplantation: how close are we? Diabetes 2012;61:3046–3055pmid:23172951
    OpenUrlFREE Full Text
  12. ↵
    1. Stanekzai J,
    2. Isenovic ER,
    3. Mousa SA
    . Treatment options for diabetes: potential role of stem cells. Diabetes Res Clin Pract 2012;98:361–368pmid:23020931
    OpenUrlCrossRefPubMed
  13. ↵
    1. Godfrey KJ,
    2. Mathew B,
    3. Bulman JC,
    4. Shah O,
    5. Clement S,
    6. Gallicano GI
    . Stem cell-based treatments for Type 1 diabetes mellitus: bone marrow, embryonic, hepatic, pancreatic and induced pluripotent stem cells. Diabet Med 2012;29:14–23pmid:21883442
    OpenUrlCrossRefPubMed
  14. ↵
    1. Domínguez-Bendala J,
    2. Lanzoni G,
    3. Inverardi L,
    4. Ricordi C
    . Concise review: mesenchymal stem cells for diabetes. Stem Cells Transl Med 2012;1:59–63pmid:23197641
    OpenUrlAbstract/FREE Full Text
  15. ↵
    1. Bonifacio E
    . Immunotherapy in type 1 diabetes: a shorter but more winding road? Diabetes 2012;61:2214–2215pmid:22923646
    OpenUrlFREE Full Text
  16. ↵
    1. Nørgaard K,
    2. Scaramuzza A,
    3. Bratina N,
    4. et al
    . Routine Sensor-Augmented Pump Therapy in Type 1 Diabetes: The INTERPRET Study. Diabetes Technol Ther 2013 [Epub ahead of print]pmid:23438304
    OpenUrlPubMed
    1. Ly TT,
    2. Nicholas JA,
    3. Retterath A,
    4. Davis EA,
    5. Jones TW
    . Analysis of glucose responses to automated insulin suspension with sensor-augmented pump therapy. Diabetes Care 2012;35:1462–1465pmid:22584133
    OpenUrlAbstract/FREE Full Text
    1. Pickup JC
    . Insulin-pump therapy for type 1 diabetes mellitus. N Engl J Med 2012;366:1616–1624pmid:22533577
    OpenUrlCrossRefPubMedWeb of Science
  17. ↵
    1. Agrawal P,
    2. Welsh JB,
    3. Kannard B,
    4. Askari S,
    5. Yang Q,
    6. Kaufman FR
    . Usage and effectiveness of the low glucose suspend feature of the Medtronic Paradigm Veo insulin pump. J Diabetes Sci Tech 2011;5:1137–1141pmid:22027306
    OpenUrlAbstract/FREE Full Text
  18. ↵
    1. Breton M,
    2. Farret A,
    3. Bruttomesso D,
    4. et al.,
    5. International Artificial Pancreas Study Group
    . Fully integrated artificial pancreas in type 1 diabetes: modular closed-loop glucose control maintains near normoglycemia. Diabetes 2012;61:2230–2237pmid:22688340
    OpenUrlAbstract/FREE Full Text
View Abstract
PreviousNext
Back to top
Diabetes: 62 (5)

In this Issue

May 2013, 62(5)
  • Table of Contents
  • About the Cover
  • Index by Author
Sign up to receive current issue alerts
View Selected Citations (0)
Print
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for your interest in spreading the word about Diabetes.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Gene Therapy for Type 1 Diabetes Moves a Step Closer to Reality
(Your Name) has forwarded a page to you from Diabetes
(Your Name) thought you would like to see this page from the Diabetes web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Gene Therapy for Type 1 Diabetes Moves a Step Closer to Reality
Timothy O’Brien
Diabetes May 2013, 62 (5) 1396-1397; DOI: 10.2337/db13-0348

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Add to Selected Citations
Share

Gene Therapy for Type 1 Diabetes Moves a Step Closer to Reality
Timothy O’Brien
Diabetes May 2013, 62 (5) 1396-1397; DOI: 10.2337/db13-0348
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • ACKNOWLEDGMENTS
    • Footnotes
    • REFERENCES
  • Figures & Tables
  • Info & Metrics
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Lifting the Veil on the “Phosphate Flush,” a Cryptic Phenomenon of Experimental Pancreatic Islet Physiology
  • Window of Opportunity: Targeting ANGPTL4 Improves Triglyceride Levels in Maternal Obesity During Pregnancy
  • New Antidiabetes Agent Targeting Both Mitochondrial Uncoupling and Pyruvate Catabolism: Two Birds With One Stone
Show more Commentary

Similar Articles

Navigate

  • Current Issue
  • Online Ahead of Print
  • Scientific Sessions Abstracts
  • Collections
  • Archives
  • Submit
  • Subscribe
  • Email Alerts
  • RSS Feeds

More Information

  • About the Journal
  • Instructions for Authors
  • Journal Policies
  • Reprints and Permissions
  • Advertising
  • Privacy Policy: ADA Journals
  • Copyright Notice/Public Access Policy
  • Contact Us

Other ADA Resources

  • Diabetes Care
  • Clinical Diabetes
  • Diabetes Spectrum
  • Scientific Sessions Abstracts
  • Standards of Medical Care in Diabetes
  • BMJ Open - Diabetes Research & Care
  • Professional Books
  • Diabetes Forecast

 

  • DiabetesJournals.org
  • Diabetes Core Update
  • ADA's DiabetesPro
  • ADA Member Directory
  • Diabetes.org

© 2021 by the American Diabetes Association. Diabetes Print ISSN: 0012-1797, Online ISSN: 1939-327X.