Key Academic Groups
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Dr. Virginia E. Kimonis:
Dr. Kimonis received her medical degree from Southampton Medical School in 1976, completed her training in pediatrics and general practice at leading institutions in the UK. In the US she completed training in advanced pediatrics at Massachusetts General Hospital/ Harvard Medical School. Her fellowship in biochemical and clinical genetics was at the National Institute of Health, John’s Hopkins and National Children’s Hospital. She was the Division Chief of Genetics and Genomic Medicine at SIU School of Medicine, Springfield, IL and at UCI School of Medicine, Irvine, CA. Her research interests encompass rare genetic neuromuscular disorders, in addition to other rare diseases.
Kimonis Lab: The Kimonis Laboratory, part of the Division of Genetics & Genomic Medicine at UCI School of Medicine, investigates genetic causes and treatments for rare muscle diseases such as rimmed vacuolar myopathy caused by HSPB8 variants, and inclusion body myopathy caused by VCP variants and other genetic disorders.
The lab's clinical research spans genetic causes, natural history, and treatments for rare diseases, including hereditary myopathies, lysosomal storage diseases, and Prader-Willi Syndrome, and other rare genetic disorders.
Since discovering the link between Inclusion Body Myopathy and HSPB8 gene mutations in the first family, the lab generated CRISPR mouse models, induced pluripotent stem cell (iPSCs) to generate myoblasts or muscle cells. These important tools are used for developing novel treatments like colchicine, arimoclomol, and gene targeting technology for HSPB8 myopathy.
Alyaa Shmara:
Alyaa is a postdoctoral fellow at the laboratory of Dr. Virginia Kimonis at UCI. Her research focus is studying the mechanisms underlying hereditary inclusion body myopathies associated with Valosin Containing Protein (VCP) and Heat Shock Protein B8 (HSPB8) mutations. She is heavily involved in investigating therapeutic approaches using FDA approved medications, small molecules, and gene therapy with potential to ameliorate pathology in myopathy mouse models.
She also conducts clinical research in Lysosomal Storage Diseases and has completed a Lysosomal Storage Diseases fellowship at UCI’sDepartment of Pediatrics, Division of Genetics and Genomic Medicine from 11/2021-12/2022.
She serves as a patient advocate for Cure HSPB8 myopathy and leads the effort of raising awareness and increasing patient identification of this rare disease.
Alyaa Shmara (researchgate.net)
Pallabi Pal, Ph.D., Project Scientist
Research Interest: Therapeutic strategies of genetic neuromuscular disorders
The underlying mechanisms and the treatment for HSPB8 associated rimmed vacuolar myopathies associated with muscle atrophy and early demise remain to be elucidated. Her goal is to develop a potent therapy to stop/reduce the progression of rimmed vacuolar myopathy. To investigate in vitro the molecular mechanism of HSPB8-associated myopathy and to assess the potential of new treatments, patient iPSC-derived myoblasts are utilized. She is recapitulating the pathogenic phenotype of patient-derived iPSCs differentiated into muscle cells. Compounds that stimulate autophagy favor the removal of protein aggregates. She is currently using an autophagy modifier to facilitate removal of protein aggregates by stimulating the autophagy pathway. Successful completion of the present mechanistic and translational study will pave the way for the treatment of HSPB8-associated inclusion body myopathy and will also benefit other related disorders.
Dr. Lan Weiss
A scientist currently affiliated with the University of California, Irvine. Holding a Doctor of Medicine degree from Hue University, Vietnam, and a Doctor of Philosophy in Human Genetics from Nagasaki University, Japan, Dr. Weiss brings a wealth of knowledge to her current role. Since joining the Kimonis lab in 2016, Dr. Weiss has dedicated her research efforts to unraveling the pathological mechanisms underlying hereditary Rimmed Vacuolar Myopathy associated with mutations in the Heat Shock Protein B8 (HSPB8) gene. Her primary objective is to make significant contributions to the development of a cure for this debilitating disease.
Dr. Weiss is particularly enthusiastic about harnessing the potential of Adeno-Associated Viruses (AAV), renowned for their proven safety and efficacy, to deliver therapeutic genes specifically to the affected muscles—the primary organ impacted in many HSPB8 patients. Additionally, she actively explores the realm of cell therapy, which involves the engraftment of healthy cells to restore or improve muscle function. Her research unfolds across two pivotal pre-clinical platforms: Patient-induced pluripotent stem cell (iPSC)-derived skeletal muscle progenitor cells and the CRISPR Cas knock-in Hspb8 mouse model. This multidimensional approach reflects her dedication to advancing the comprehension and treatment of HSPB8-related conditions.
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Angelo Poletti, PhD
Professor Angelo Poletti is a Full Professor of Experimental Biology at the University of Milan, specializing in the role of the protein quality control system in neurodegenerative and neuromuscular diseases. He obtained his Italian Laurea and subsequent degrees in Chemical and Pharmaceutical Technology and Experimental Endocrinology, including a Ph.D. in Endocrinological Sciences. With a background that includes three years of research at Baylor College of Medicine in Houston, TX, USA, Professor Poletti now directs the research laboratory of Experimental Biology at the Dipartimento di Scienze Farmacologiche e Biomolecolari and the Centre of Excellence on Neurodegenerative Diseases at the University of Milan, Italy. At the same University, he also teaches 'Experimental Biology' and 'Cell Biology' to students of Biotechnology and Pharmaceutical Chemistry.
Dr. Poletti's research group focuses on several key projects. They investigate motoneuronal degeneration in Spinal and Bulbar Muscular Atrophy (SBMA or Kennedy's disease), exploring neurotoxic effects induced by mutations in the androgen receptor. Additionally, they study motoneuronal degeneration in Amyotrophic Lateral Sclerosis (ALS), particularly the impact of mutations in the Superoxide dismutase (SOD1) and in the C9ORF72 genes, as well as the alterations related to the aberrant TDP-43 protein behavior. More recently the group also became interested in neuromuscular diseases and myopathies caused by mutations in the genes encoding for a small heat shock protein (HSPB8) and its co-chaperone BAG3, proteins involved in a peculiar form of autophagy, named chaperone-assisted selective autophagy (CASA). His lab recently identified a protective mechanism of a small heat shock protein (HSPB8) mediated by autophagy, which efficiently clears misfolded protein from cells, broadening our understanding of neurodegenerative diseases. Poletti’s group also delves into the androgenic and estrogenic control of prostate and breast cancer cell growth, examining the mechanisms of action of androgen and estrogen receptors. Moreover, they explore the effects of gonadal steroids on motoneuronal functions, characterizing receptors and steroid-inducible genes in cultured motoneuronal cells.
Barbara Tedesco, PhD
Barbara Tedesco is an Assistant Professor of Experimental Biology at the Dipartimento di Scienze Farmacologiche e Biomolecolari and the Centre of Excellence on Neurodegenerative Diseases at the University of Milan. Her research focuses on the role of proteostasis imbalance in diseases affecting the neuromuscular system.
She obtained her bachelor's and master’s degrees in Pharmaceutical Biotechnology and Drug Biotechnology, respectively. Then, she obtained a PhD in Integrative Biomedical Research.
She joined the laboratory of Professor Angelo Poletti as an undergraduate student, and she completed my predoctoral and doctoral studies by investigating the mechanisms at the basis of motoneuron diseases, neuropathies, and myopathies.
Her predoctoral and doctoral studies have been primarily devoted to investigating the molecular behavior of mutants and variants of the co-chaperone BAG3 and the small heat shock protein HSPB8, which are associated with neuropathies and (cardio)myopathies.
After the PhD degree, she obtained a fellowship from the IRCCS Istituto Neurologico Carlo Besta (Milan), to investigate mutations affecting the neuro-specific kinesin KIF5A gene, which have been identified in different neurologic and neurodegenerative disorders.
Her current studies are also dedicated to investigating the pathogenic mechanisms and therapeutic strategies in spinal and bulbar muscular atrophy and amyotrophic lateral sclerosis, with a particular interest in the molecular mechanisms regulating protein translation machinery.
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Dr. Michio Hirano currently serves as Chief of the Neuromuscular Division at Columbia University Medical Center's Neurology Department, Co-Director of the CUMC Muscular Dystrophy Association clinic, and Director of the H. Houston Merritt Center for Muscular Dystrophy and Related Diseases.
In addition to his clinical responsibilities, Dr. Hirano's research primarily centers on mitochondrial diseases and genetic myopathies. Regarding HSPB8 myopathy, Dr. Hirano and his colleagues are working with cultured skin fibroblasts to understand chaperone-assisted selective autophagy (CASA) in pathogenic cells compared to controls. They have profiled the expression of autophagy-related proteins in the cultured cells and are currently conducting drug screening studies to identify whether candidate drugs are predicted to ameliorate or worsen the aberrant autophagy in the HSBP8-mutant cells.