Significant Accomplishments

Long-Term (IGF-1) Growth Factor Replacement Therapy is Safe and Effective

A study led by Philippe Backeljauw, MD, published in July 2013 in Hormone Research in Paediatrics, reports that long-term therapy with recombinant human insulin-like growth factor-1 (IGF-1) appears to be effective and safe as a replacement therapy in children with short stature due to severe IGF-1 deficiency (IGFD), a disorder caused by resistance to the effects of growth hormone. Previous reports from this long-term study led to U.S. and European approvals for this treatment. This study reports final height data after tracking participants as they grew to adulthood. For some children with severe short stature, IGF-1 therapy is the only effective option because they are resistant to exogenous growth hormone therapy. Participants who received IGF-1 doses of 120 μg/kg twice daily experienced significant increases in height velocity. Although most did not reach normal heights, many achieved an adult height significantly greater than expected in the absence of therapy. Because the spectrum of growth hormone insensitivity is wider than the patients reported upon in this study, further investigation into the therapeutic applicability of IGF-1 in patients with varying degrees of IGFD is warranted.

IGF-1 Therapy Improves Height for Boys with Duchenne Muscular Dystrophy

Backeljauw and Meilan Rutter, MD, FRACP, Endocrinology, also worked with James Collins, MD, PhD, and Brenda Wong, MD, MBBS,  Neuromuscular Center, to study recombinant human insulin-like growth factor-1 (IGF-1) as a potential treatment in Duchenne muscular dystrophy (DMD) patients. This progressive, incurable muscle disorder affects one in 3,500 boys. DMD is treated with glucocorticoids (GC), which improve motor function, but cause significant endocrine adverse effects such as growth failure and insulin resistance. IGF-1 is used to treat children with certain growth disorders. It also has been shown to improve muscle strength and survival in genetically engineered mice with DMD. The investigators hypothesized that IGF-1 therapy would improve statural growth and preserve muscle function in GC-treated DMD boys. They found that six months of a once-daily injection of IGF-1 therapy doubled height velocity and significantly increased height standard deviation scores compared to controls. Markers of insulin resistance also improved. However, there was no difference in motor functional outcomes.

Functional Hormone Production in Human Intestine Generated from Pluripotent Stem Cells

Jonathan Howell, MD, PhD, works with James Wells, PhD, to understand the nature of the human intestinal incretin hormones, GIP and GLP-1, which play an important role in regulating glucose homeostasis and are often dysfunctional in diabetes. Wells’ lab has established a method for differentiating human pluripotent stem cells into intestinal organoid tissue, which serves as a novel model for studying intestinal development and function. Howell has shown that the proximal-distal regional identity of intestinal organoids is regulated by bone morphogenetic protein (BMP) signaling, such that BMP inhibition promotes a proximal (small intestinal) fate, whereas activation results in a distal (large intestinal) fate. Importantly, there is segregation of intestinal incretin hormone producing cells within regionalized organoids, which mimics normal human intestine in vivo. These findings have allowed for the study human intestinal incretin pathology in the context of diseases such as diabetes and cystic fibrosis. Howell and colleagues are investigating the dynamics of hormone cell emergence in developing human intestinal tissue, the transcriptional network that controls individual hormone-specific cell fate, and the ability of experimental incretin-secreting drugs to elicit hormone responses. Results of this work will potentially impact new therapeutic regimens for patients with intestinal diseases and disorders of glucose homeostasis.