Gene Therapy for Diabetes Mellitus Jeong H. Park, M.D., Ph.D. - - PowerPoint PPT Presentation

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Gene Therapy for Diabetes Mellitus Jeong H. Park, M.D., Ph.D. - - PowerPoint PPT Presentation

Aug 28, 2023 120 likes •577 views

Gene Therapy for Diabetes Mellitus Jeong H. Park, M.D., Ph.D. Department of Internal Medicine, Pusan Paik Hospital, College of Medicine, Inje University, Busan, Korea Disclaimer 1. I received only official lecture fee from Korean Diabetes

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Gene Therapy for Diabetes Mellitus

Jeong H. Park, M.D., Ph.D.

Department of Internal Medicine, Pusan Paik Hospital, College of Medicine, Inje University, Busan, Korea

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Disclaimer

  • 1. I received only official lecture fee from Korean Diabetes Association for this

talk

  • 2. I do not own venture corporations, and hold any stocks of pharmaceutical

companies

  • 3. Because my concerns are concentrated in the non-viral gene delivery system,

my talk might include biased opinions for the gene therapy researches using viral gene carriers

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Contents

  • 1. Definition & Current Status of Gene Therapy Researches
  • 2. Gene Therapy for Type 2 Diabetes Mellitus
  • 3. Gene Delivery Systems & Potential for the Commercial Novel Therapies
  • 4. UTMD (Ultrasound Micro-bubble Destruction) Gene Therapy
  • 5. Our Previous & Current Works
  • 6. Future Perspectives
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Gene Therapy

Therapeutic Nucleic Acids Gene Delivery Techniques Therapeutic Nucleic Acids

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Kim et al. Mol Therapy 2007;16:237-243

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  • Comparisons with Conventional Therapy
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Gene Therapy for type 2 Diabetes ?

  • Polygenic disorder : Gene – Environmental Interaction
  • What is the canditate gene ?
  • Causes ? or just Risk Factors ?
  • Insulin deficiency : Insulin GT, Beta cell rejuvenation, regeneration
  • Insulin resistance : Hepatic glucose production, adipocytokines
  • CNS, neural regulation : leptin signaling

Diabetic Symptom Palliation rather than CURE

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Gene Therapy for type 2 Diabetes ?

Lancet 2009;6736(09):60448-7

G T

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Gene Therapy

Therapeutic Nucleic Acids Gene Delivery Techniques Therapeutic Nucleic Acids Gene Delivery Techniques

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  • !

Gene Delivery Methods

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Chemical Calcium-phosphate transfection DEAE-dextran transfection Physical Electroporation Microinjection Particle bombardment Fusion Liposomes Receptor-mediated endocytosis DNA-protein complexes Viral envelope/capsid-DNA complexes Recombinant viruses Adenovirus Adeno-associated virus (AAV) Herpes simplex virus Human immunodeficiency virus (HIV) Moloney murine leukemia virus Vaccinia virus Low Low Low High High Low High High High High Low High High High Low Low Low Low Low Low Low Low Low High Low High High Low

Transduction efficiency Integration efficiency

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Barriers for Gene Therapy

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Tragedies in Early Clinical Trials

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  • Requirements for the Success in Real World
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Requirements for the Success in Real World

  • SU

metformin DPP-IV incretin SGL2 TZD insulin

superiority practicalize investment

Gene Therapy

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Safest method in Gene Therapy ?

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UTMD: Sonoporation

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Efficiency vs Toxicity.. Sonoporation

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Journal of Drug Targeting 2008;16(10):773-779

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Journal of Drug Targeting 2008;16(10):773-779

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Expert Opin Drug Deliv 2010;7(3):321-330

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. One of the main advantages of drug or gene delivery by sonoporation is to achieve site specificity with negligible local and systemic toxicities, by the

  • ptimization of parameters of ultrasound and microbubbles.

. The dynamic characteristics of ultrasound that induce cell membrane porosity can be controlled by ultrasonic factors such as frequency, intensity and duration. . The induction of microbubble cavitation by ultrasound has been considered a major mechanism of delivery, which carries non-permeable macromolecules across the cell membrane. . Ultrasound can act synergistically with other vector systems in order to have several advantages, such as low cytotoxicity, high target selectivity, low immunogenicity and repeatable application.

Expert Opin Drug Deliv 2010;7(3):321-330

UTMD: Sonoporation

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. Gene delivery by sonoporation could be a possible therapeutic alternative in current cancer treatment. . Non-invasive specific gene transfection into the deep seated internal organ is very difficult. Sonoporation might be used for this purpose and the possibility for the application of this technique to the various kinds of diseases would be promising. . Particularly suited for the various localized diseases and the diseases requiring limited transfection into the deep-seated organs or tissues, sonoporation could be used successfully in clinical practice in the near future. . Along with its superior safety profile, sonoporation might be regarded as a pioneering technique that could move gene therapy a step closer to clinical medicine.

Expert Opin Drug Deliv 2010;7(3):321-330

UTMD: Sonoporation

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M Calos et al. JMB, 2004

J Cont Release 2006;114:118-125

Improving Gene Expression - Minicircle

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J Kor Diabetes Assoc 2007;31:465-471

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J Kor Diabetes Assoc 2007;31:465-471

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Kor Diabetes J 2008;32:131-140

Improving Gene Expression - Modification

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Kor Diabetes J 2008;32:131-140

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Kor Diabetes J 2008;32:131-140

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Pharm Res 2009;26(4):794-801

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Pharm Res 2009;26(4):794-801

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Pharm Res 2009;26(4):794-801

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Pharm Res 2009;26(4):794-801

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Pharm Res 2009;26(4):794-801

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J Gene Med 2012;14:272-278

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J Gene Med 2012;14:272-278

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J Gene Med 2012;14:272-278

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β-Cell Function Continues to Decline Regardless of Intervention in T2DM

UKPDS Group. Diabetes. 1995; 44: 1249–1258. 20 40 60 80 100 –5 –4 –3 –2 –1 1 2 3 4 5 6 Years Since Diagnosis β-Cell Function (%)*

Progressive loss of β-cell function

  • ccurs prior to diagnosis

Metformin (n=159) Diet (n=110) Sulfonylurea (n=511)

The Last Topic – Type 2 Diabetes Remission

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β-Cell Function Continues to Decline Regardless of Intervention in T2DM

UTMD-Pancreatic β cell targeting

PA Grayburn et al. Gene Therapy 2010

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PA Grayburn et al. Gene Therapy 2010

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PA Grayburn et al. Gene Therapy 2010

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β-Cell Function Continues to Decline Regardless of Intervention in T2DM

Summary & Conclusion

  • 1. Gene Therapy for Diabetes
  • Researchers, Government, Corporation, Investor, Patency, Market etc.
  • 4. Safety, rather than efficacies
  • Distinction, between Science & Business
  • 3. State of the Art
  • From dreaming to design, based on valid technologies
  • 2. Scanty Possibility for Glorious Victory
  • Genetics Researches, Competition with many available modalities