CommentaryType 1 Diabetes

Evaluating Preclinical Efficacy

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Science Translational Medicine  17 Aug 2011:
Vol. 3, Issue 96, pp. 96cm22
DOI: 10.1126/scitranslmed.3002757
  • Table 1. Crossing the translational divide.

    Shown below are steps for improving the translational potential for therapeutic intervention studies of disease reversal in NOD mice. Initial recommendations for consideration are in italics.

    Establish parameters for experimental design and reporting.
    • Minimum group sample size for analysis.
    o Minimum of 12 animals per group for calculation of disease frequency (that is, remissions).
    • Definition for control groups (use of placebo controls versus historical controls).
    o Must use contemporaneous controls subject to similar handling and procedures as treatment groups.
    • Age limits (earliest and latest age for mice included in study).
    o Only use animals with disease onsets ≥10 weeks and ≤24 weeks. In addition, mice should be randomized to treatment groups to assure no age bias exists amongst treatment groups (ages, with range and SE, should be reported for all treatment groups).
    • Reporting of NOD colony frequency for type 1 diabetes.
    o Background (unmanipulated) frequency of NOD colony within contemporaneous time period (≤ 2 years) should be reported.
    • Standardize time from hyperglycemic onset to initiation of therapeutic intervention.
    o 0 to no more than 48 hours after diabetes onset for studies of T1D reversal.
    Impart standards for diagnosis and treatment.
    • Method for defining “diabetes” (hyperglycemia in blood versus glycosuria).
    o Hyperglycemia using blood obtained from IACUC approved method (such as tail vein).
    • Definition of diabetes onset using blood glucose (for example, specific mg/dl value and number of occasions in hyperglycemic range).
    o ≥250mg/dl, on two occasions, separated by 16 to 24 hours, and no more than 48 hours.
    • Agreement on insulin therapy post-diagnosis (address question of use, route of administration, type of insulin, and duration of administration).
    o Must provide insulin treatment by IACUC approved means (such as insulin injections, insulin pellet, or pump) capable of imparting diabetes management (normoglycemia/mild hyperglycemia, acceptable with local IACUC) for a period until disease reversal occurs or intervention is considered a failure.
    Define principles to assess therapeutic efficacy.
    • Blood glucose at time of treatment onset should be reported for all study groups.
    o Efficacy data must compare starting blood glucose values for all treatment groups to assure there is no bias.
    • Adopt universal definition for “reversal” (what level of dysglycemia, if any, would be considered a success as well as a failure).
    o Achieve three blood glucose levels of <250 mg/dl, separated by 16 to 24 hours, within a 3-day period, taking into account the potential influence of insulin therapy (daily insulin treatment versus the use of insulin pellets will potentially require different means of analysis).
    • Standard duration for follow-up (number of days animals must be monitored to assure reversal).
    o Monitor animals for at least 90 days, with blood glucose assessments at least once per week.

Additional Files

  • Supplementary Material for:

    Evaluating Preclinical Efficacy

    Mark A. Atkinson*

    *To whom correspondence should be addressed. E-mail: atkinson{at}ufl.edu

    Published 17 August 2011, Sci. Transl. Med. 3, 96cm22 (2011)
    DOI: 10.1126/scitranslmed.3002757

    Supplementary Material for this manuscript includes the following:

    Table S1. Attempts to reverse Type 1 diabetes in NOD mice between 1990 and 2010. An influence of human study results on the design of experiments in mice.

    [Download Table S1]

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