Recent Discoveries at UMMS

Phase 1/2 Clinical trial of gene therapy to correct Leber Congenital Amaurosis

In June 2009, Dr. Shalesh Kaushal and his team of UMass investigators initiated a phase 1/2 clinical trial to assess safety of a recombinant adeno-associated virus (AAV) expressing the normal RPE65 gene in patients with Leber Congenital Amaurosis.

Discovery of a novel therapeutic agent for the treatment of malignant melanoma

Dr. Michael Green, Professor of Gene Function and Expression, Investigator, Howard Hughes Medical Institute is Director of the RNAi Reagent Core Facility. Dr. Green performed a genome-wide RNAi screen to identify genes required for oncogene BRAF-mediated senescence/apoptosis. He identified 17 different genes, including IGFBP7, an insulin-like growth factor binding protein. This secreted protein is turned off in malignant melanomas with a mutation in the BRAF oncogene. Treatment of these malignant melanomas with IGFBP7 in vitro and in vivo results in apoptosis of the tumor cells

Members of the UMCCTS Translational Navigator Program Committee reviewed the experimental results and agreed that IGFBP7 should move forward in the preclinical pathway toward first in human studies. Drs. Sullivan and Flotte are currently working with Dr. Green to identify funding necessary for GMP production of IGFBP7and pharmacokinetic and toxicology preclinical studies. Chris Perkin and his colleagues at CRL are designing the protocol for the preclinical studies.

Development of an oral delivery mechanism for RNAi therapeutics

Drs. Michael Czech and Gary Ostroff in the Program in Molecular Medicine have been able to encapsulate siRNAs in particles composed of yeast cell wall glucan. Their experiments have demonstrated that these particles can be orally delivered to mice and protect mice from lethal challenge with lipopolysaccharide (LPS) by siRNA silencing of tumor necrosis factor alpha (TNFα) the mediator of LPS induced lethal shock.

Consultation with the UMCCTS Co-Pilot Program led to the collaboration between the Czech/Ostroff laboratories and Dr. Ellen Gravallese who studies immunologic mechanisms in arthritis models. These investigators successfully applied to the UMCCTS Pilot Project Program and received funding to study the oral delivery of siRNA directed at silencing the TNFα gene in the mouse model of arthritis. 

Development of RNAi Therapy for the treatment of amyotrophic lateral sclerosis (ALS)

Dr. Robert Brown, Professor and Chair, Department of Neurology is one of the world’s authorities on ALS. Dr. Brown’s laboratory identified one of the genes associated with ALS, cytosolic superoxide dismutase, or SOD1. Current views suggest that the mutation of SOD1 causes misfolding of the SOD1 protein and resulting toxicity to the neuron. 

Recent studies by Dr. Zuoshang Xu, Professor of Biochemistry and Molecular Pharmacology have
demonstrated that RNAi molecules can silence mutant SOD1 in vivo and increase survival time in the mouse model of ALS. Drs. Brown and Xu have collaborated in the design of RNAi molecules for a trial in humans with mutant SOD1 associated ALS. First in human studies of RNAi in ALS are currently underway at UMass.

Development of a Novel Anti-Cancer Agent

In 2005, Dr. Dario Altieri, Professor and Chair, Department of Cancer Biology engineered a compound called Sheperdin which blocks the interaction of the protein survivin (discovered in 1997 by Altieri) with heat shock protein 90 and results in the destruction of tumor cells and inhibition of tumor growth in murine models of human cancer. Dr. Altieri was awarded an NCI RAID grant in 2005 for clinical development of Shepherdin.