Mount Sinai Scientists recieve grant for IGF trials

Mount Sinai Scientists recieve NHI grant to study clinical benefit of IGF-1 in children with PMS

Published on August 27, 2013 at 12:49 AM ·

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Scientists at the Seaver Autism Center at the Icahn School of Medicine at Mount Sinai have received a grant from the National Institutes of Health (NIH) to study Insulin-Like Growth Factor-1 (IGF-1), a promising treatment for a subtype of autism called Phelan McDermid Syndrome (PMS). The grant will allow researchers to expand upon an ongoing study assessing the clinical benefit of IGF-1 in children with this severe type of autism.
IGF-1 is a commercially-available compound for growth deficiency that is known to promote nerve cell survival as well as synaptic maturation and plasticity. The primary aim of the study is to target core features of PMS, including social withdrawal and language impairment, which will be measured using both behavioral and objective assessments. So far, nine patients have participated in a pilot study to assess safety and feasibility of IGF-1. The Seaver Autism Center team hopes to enroll 18 more participants with support from the NIH grant, in order to establish statistically significant clinical benefit of IGF-1. The NIH will provide more than $750,000 over three years to study IGF-1.
With the grant, Alex Kolevzon, MD, Clinical Director the Seaver Autism Center, will continue to enroll children ages 5 to 12 years old who have PMS in this double-blind, placebo-controlled crossover study. Patients will first receive three months of either active medication or three months of placebo. After a four-week break, patients who received active medication first will then receive three months of placebo, and patients who were first randomized to placebo will receive three months of active medication. Future trials are planned to explore the utility of IGF-1 in ASD without SHANK3 deficiency, the hallmark genetic mutation in PMS.
Dr. Kolevzon has also received a grant for $25,000 from the Autism Science Foundation to study IGF-1 as a treatment for idiopathic autism.

"IGF-1 has the potential to be effective in treating Phelan-McDermid Syndrome and other types of autism spectrum disorder," said Dr. Kolevzon. "We are very pleased that the NIH and the Autism Science Foundation have recognized this by providing us funding to continue our work in bringing this medication to our patients."
The clinical studies with IGF-1 are supported by studies in a genetically modified mouse with a mutation in SHANK3. These studies carefully examined brain function in the mice when SHANK3 was mutated, and provided preclinical evidence for a beneficial effect of IGF-1. Deficits in nerve cell communication were reversed and deficiencies in adaptation of nerve cells to stimulation, a key part of learning and memory, were restored. These studies were reported the April 27th issue of Molecular Autism.
Side effects of IGF-1 administration include low blood sugar, liver function abnormalities, and increased cholesterol and triglyceride levels. Study subjects will undergo rigorous safety screening before they are enrolled in the trial, and will be carefully monitored every two to four weeks with safety and efficacy assessments.

SOURCE Mount Sinai Medical Center

Below is the conclusion of the testing they performed to recieve this grant for Human Trials:

We first tested an active peptide derivative of IGF-1, (1–3)IGF-1, which has been shown to cross the blood–brain barrier and rescue Rett syndrome symptoms in Mecp2-deficient mice [11]. We observed that intraperitoneal injections at 10 μg/g/day for 2 weeks restored normal hippocampal LTP in Shank3 heterozygous mice but had no effect on wild-type mice (repeated measures ANOVA was used to analyze the last five time points, F(3,11) = 6.07, P = 0.011). In post hoc analyses, vehicle-treated heterozygous mice were significantly different from wild-type mice (P = 0.004), while (1–3)IGF-1 treated heterozygous mice were not (P = 0.66). Furthermore, peptide treatment reversed deficits in the mean slope of the input/output (I/O) function (Figure 1b) (one-way ANOVA, F(3,19) = 4.25, P = 0.02). Vehicle-treated heterozygous mice were significantly different from vehicle-treated wild-type mice (P = 0.001), while (1–3)IGF-1 treated heterozygous mice were not different from vehicle-treated wild-type (P = 0.89), and there were no significant differences between vehicle-treated wild-type mice and wild-type mice treated with IGF-1 (P = 0.812), so further studies used just three conditions.
We next administered full-length IGF-1, like that used in children with short stature due to primary IGF-1 deficiency, by intraperitoneal injection at 240 μg/kg/day, starting at PND 13 to 15 and continuing for 2 weeks (Figure 2a). This dose, chosen because it represents the maximum dose according to the current FDA label for IGF-1, was effective in rescuing deficits in LTP (repeated measures ANOVA was used to analyze the last five time points, comparing heterozygous mice with and without IGF-1, F(1,6)=28.04, P=0.002). In contrast, lower dose IGF-1 (120 μg/kg/day for 2 weeks) was associated with more modest reversal of deficits in LTP (for the last five time points: F(1,6)=2.62, P=0.012), showing a dose–response effect and providing preclinical dosing information.
Specific deficits in the glutamate AMPA receptor component of neural signaling [5] were also reversed by a 2-week treatment of 240 μg/kg/day full-length IGF-1 (Figure 2b). The mean slope of the I/O function was 0.50 ± 0.14 for wild-type, 0.34 ± 0.06 for Shank3 heterozygotes and 0.61 ± 0.059 for IGF-1 injected heterozygotes (one-way ANOVA, F(2,9) = 8.62, P = 0.008). In post hoc analyses, vehicle-treated heterozygous mice were significantly different from vehicle-treated wild-type mice (P = 0.039), while IGF-1-treated heterozygous mice were not different from vehicle-treated wild-type mice (P = 0.12).
Patients with SHANK3-haploinsufficiency frequently present with hypotonia and motor deficits of variable severity, and we have observed subtle motor deficits in Shank3-heterozygous mice [5,7]. After treating male heterozygous mice with 240 μg/kg/day for 2 weeks, we observed enhanced motor performance following treatment (Figure 2c) (F(2,20) = 3.98, P = 0.03).
Our results provide preclinical evidence for a beneficial role for IGF-1 in SHANK3-haploinsufficiency. Moreover, as there is emerging evidence that the SHANK3 pathway and the postsynaptic density, which it helps sculpt, play a role in many neurodevelopmental disorders, as evidenced by large-scale genetic, proteomic, and gene expression studies [3,4,14], therapies for SHANK3 deficiency and synaptic development represent important targets that could have a widespread positive impact for neurodevelopmental disorders. The beneficial effects of IGF-1 in models of Rett syndrome [11,15] are consistent with this hypothesis.
There are some limitations to the current study. We, and others working with similar Shank3-deficient mice, see only limited behavioral abnormalities, with none except for rotarod deficits at the ages where we carried out the IGF-1 treatments and electrophysiological studies. For this reason, the phenotypes we measure are somewhat limited. In addition, a mechanistic understanding of the neuronal effects of IGF-1 has eluded the neuroscience community and we cannot precisely explain how IGF-1 reverses the deficits observed. We do hope, however, that our findings, together with those on IGF-1 in Rett syndrome models, may help spur further research on the action of IGF-1 in the CNS. We did not see any effect produced by the (1–3)IGF-1 peptide on control animals but we did not test the effects of full-length IGF-1 on wild-type mice. There could be enhanced LTP or rotarod performance in control animals following treatment with full-length IGF-1. Many drugs have effects on both healthy and non-healthy individuals and there is hence no a priori reason to assume that IGF-1 has no effect on control animals. In fact, given the positive effects of IGF-1 in Rett syndrome models it is likely that IGF-1 has a general effect on CNS function, which might also be observed in controls.
In summary, our results show that IGF-1, approved for use in children, can lead to functional improvements in a mouse model of ASD and developmental delay, representing an important preclinical step towards novel therapeutics. Clinical trials of IGF-1 in SHANK3-deficient individuals and in ASD are now underway (ClinicalTrials.gov Identifier NCT01525901).
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nothing we guinea pigs didn't already know lol. igf is amazing specifically lr3.

Its new to me Brutha.....Lovin the guinea pig comment though....lol

Presser said:

nothing we guinea pigs didn't already know lol. igf is amazing specifically lr3.

Click to expand...

seems they tend to be behind, in some aspects.

Publicised Human trials are always lagging.....I've just been behind the times with this one....Its the underground where the rubber meets the road...Guinea pigs like Presser said....Just glad I found you Hoggin MF's

Maybe they need to join the forum and save 750000 dollars lol.