Insulin-like growth factor-1 rescues synaptic and motor deficits in a mouse model of autism and developmental delay.
Haploinsufficiency of SHANK3, due to either hemizygous gene deletion (termed 22q13 deletion syndrome or Phelan-McDermid syndrome) or to gene mutation, accounts for about 0.5% of the cases of autism spectrum disorder (ASD) and/or developmental delay, and there is evidence for a wider role for SHANK3 and glutamate signaling abnormalities in ASD and related conditions. Therapeutic approaches that reverse deficits in SHANK3-haploinsufficiency may therefore be broadly beneficial in ASD and in developmental delay.
We observed that daily intraperitoneal injections of human insulin-like growth factor 1 (IGF-1) over a 2-week period reversed deficits in hippocampal α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) signaling, long-term potentiation (LTP), and motor performance that we had previously reported in Shank3-deficient mice. Positive effects were observed with an IGF-1 peptide derivative as well.
We observed significant beneficial effects of IGF-1 in a mouse model of ASD and of developmental delay.
Studies in mouse and human neuronal models of Rett syndrome also show benefits with IGF-1, raising the possibility that this compound may have benefits broadly in ASD and related conditions, even with differing molecular etiology.
Given the extensive safety data for IGF-1 in children with short stature due to primary IGF-1 deficiency, IGF-1 is an attractive candidate for controlled clinical trials in SHANK3-deficiency and in ASD.
Triggering regeneration and tackling apoptosis: a combinatorial approach to treating congenital muscular dystrophy type 1 A
Merosin-deficient congenital muscular dystrophy type 1A (MDC1A) is an autosomal recessive disorder caused by mutations in the laminin-α2 gene (OMIM: 607855).
Currently, no treatment other than palliative care exists for this disease. In our previous work, genetic interventions in the Lama2Dy-w mouse model for MDC1A demonstrated that limited regeneration and uncontrolled apoptosis are important drivers of this disease.
However, targeting one of these disease drivers without addressing the other results in only partial rescue of the phenotype. The present study was designed to determine whether utilizing a combinatorial treatment approach can lead to a more profound amelioration of the disease pathology.
To accomplish this task, we generated Bax-null Lama2Dy-wmice that overexpressed muscle-specific IGF-1 (Lama2Dy-wBax−/−+IGF-1tg). Further to test the translational potential of IGF-1 administration in combination with Bax inhibition, we treated Lama2Dy-wBax−/− mice postnatally with systemic recombinant human IGF-1 (IPLEX™).
These two combinatorial treatments lead to similar, promising outcomes. In addition to increased body and muscle weights, both transgenic overexpression and systemic administration of IGF-1 combined with Bax-inhibition resulted in improved muscle phenotype and locomotory function that were nearly indistinguishable from wild-type mice.
These results provide a fundamental proof of concept that justifies the use of a combination therapy as an effective treatment for MDC1A and highlights a compelling argument toward shifting the paradigm in treating multifaceted neuromuscular diseases.
Researchers Identify Novel Therapy to Treat Muscular Dystrophy
June 25, 2013 — Researchers at Boston University College of Health & Rehabilitation Sciences: Sargent College have identified a combinatorial therapeutic approach that has proven effective in treating muscular dystrophy in a mouse model. The findings, published in Human Molecular Genetics, represent a paradigm shift for the treatment of muscular dystrophy as well as a host of other disabling and devastating muscle diseases.
The study was led by Mahasweta Girgenrath, PhD, assistant professor and director of the Muscle Disorders and Regenerative Biology Laboratory at BU Sargent College’s Department of Health Sciences. Boston University (BU) researchers and postdoctoral fellows Jenny Yamauchi, Ajay Kumar, Lina Duarte, and Thomas Mehuron were collaborators on this study.
Muscular Dystrophy type 1A (MDC1A) is the second most common form of congenital muscular dystrophy. Patients with this disease have poor muscle tone at birth, extremely compromised neuromuscular function, and are rarely able to walk independently. Most patients with MDC1A succumb to a premature death due to either respiratory complications or failure to thrive. Although significant strides have been made towards understanding the molecular and biochemical mechanisms underlying MDC1A, there remains no effective therapy in place to combat this lethal disease.
The research team, led by Girgenrath, hypothesized that the complex pathology seen in MDC1A may be the result of dysregulation of multiple cellular functions and processes, meaning that strategies which simultaneously target several of those mechanisms might lead to a reduction of symptoms.
“Very few studies have utilized the power of combinatorial therapy in the context of muscular dystrophy.” said Professor Girgenrath, the study’s corresponding author. “While most MD treatments are single-target therapies, we’re delving into combinations of different therapies to target multiple pathways.”
The research team studied the outcome of combining the following single mode treatments: increasing regeneration, by overexpressing muscle specific insulin like growth factor-1, IGF-1 and preventing cell death, by inhibiting the expression of Bax, a pro-apoptotic protein. In addition, to test the translational potential of this combination therapy, the researchers systemically treated Bax deficient dystrophic mice with recombinant human IGF-1 (IPLEX TM, manufactured by Insmed Inc).
By combining these two therapies, researchers found that in addition to increased body and muscle weight, mice showed enhanced locomotory capacities and remarkable improvement in muscle pathology.
The most impressive outcome was the significant resolution of inflammation and fibrosis, not seen with single mode therapies. The research team concluded that the use of this combination therapy is an effective treatment for MDC1A, highlighting a compelling argument that a combinatorial approach has a synergistic benefit and could have the potential of treating patients with congenital muscular dystrophy.
Research highlighted in this news release was funded in part by Cure CMD, Struggle against Muscular Dystrophy (S.A.M), and the Muscular Dystrophy Association (MDA).
“19.44% of ASD patients had epilepsy as compared to 2.19% in the overall hospital population (95% confidence interval for difference in percentages 13.58-14.69%), 2.43% of ASD with schizophrenia vs. 0.24% in the hospital population (95% CI 1.89-2.39%), inflammatory bowel disease (IBD) 0.83% vs. 0.54% (95% CI 0.13-0.43%), bowel disorders (without IBD) 11.74% vs. 4.5% (95% CI 5.72-6.68%), CNS/cranial anomalies 12.45% vs. 1.19% (95% CI 9.41-10.38%), diabetes mellitus type I (DM1) 0.79% vs. 0.34% (95% CI 0.3-0.6%), muscular dystrophy 0.47% vs 0.05% (95% CI 0.26-0.49%), sleep disorders 1.12% vs. 0.14% (95% CI 0.79-1.14%).”