PEREZ LAB
GENE THERAPY FOR NEURODEGENERATION
We use state-of-the-art gene editing technologies to correct pathogenic mutations
The progressive degeneration of the structure and function of the central nervous system, peripheral nervous system or musculoskeletal system is responsible for a broad range of diseases such as Parkinson's disease, Alzheimer's disease or Duchenne muscular dystrophy, which are incurable, debilitating and, ultimately, lethal. As the incidence and prevalence of these diseases increase with age, they will become major challenges for medicine and public health in future years.
The genome editing revolution that occurred in the past 5 years has enabled the creation of technologies for editing the genome of living cells. Gene editing tools have proven to be effective for activating, repressing or knocking out genes, integrating DNA at target sites or even introducing single base modifications at specific sequences. The wide range of genomic modifications that can be accomplished with gene editing tools enables multiple strategies for treating human diseases.
Viral gene delivery systems can now safely and effectively carry nucleic acids to target cell populations within living organisms. AAV vectors, in particular, possess low pathogenicity and have demonstrated efficacy in numerous clinical trials, including ones for hemophilia B, choroideremia, lipoprotein lipase deficiency, and Leber congenital amaurosis type II, the latter of which earned regulatory approval by the FDA in 2017.
Gene editing and gene delivery technologies have matured independently and are now primed to be applied as a cohesive suite of molecular tools for providing novel therapeutic solutions to previously incurable human diseases. Our laboratory utilizes gene editing tools to develop treatments for some of the most lethal neurodegenerative and musculoskeletal diseases.
EXPERIMENTAL FRAMEWORK
GENE EDITING TECHNOLOGY
The recent advances in genetic engineering yielded several generations of tools that enable unprecedented control over the genomes of any living cell. Zinc fingers, TALEs and, more recently, CRISPR systems can be used for introducing mutations in genes with single base resolution, for modulating gene expression at the genome or transcriptome level or even visualizing a modifying the position of specific DNA sequences in the cell nucleus. Our laboratory combines state-of-the-art gene editing technologies with novel delivery systems to develop cures for previously untreatable diseases.
AAV GENE DELIVERY SYSTEM
AAV vectors are a clinically promising gene delivery vehicle that has been shown to be an especially effective tool for delivering CRISPR technology. AAV vectors possess low pathogenicity and have demonstrated efficacy in numerous clinical trials, including ones for hemophilia B, choroideremia, lipoprotein lipase deficiency, and Leber congenital amaurosis type II, the latter of which earned regulatory approval by the FDA in 2017. We have created multiple vector systems that enable packaging and delivery of gene editing tools in vivo using AAV.
EXPERIMENTAL
FRAMEWORK
GENE EDITING TECHNOLOGY
Duchenne Muscular Dystrophy
Duchenne muscular dystrophy is a severe type of muscular dystrophy. Muscle weakness usually begins around the age of four and worsens quickly. Typically muscle loss occurs first in the thighs and pelvis followed by those of the arms. This can result in trouble standing up. Most patients are unable to walk by the age of 12 and there is no cure for Duchenne muscular dystrophy.
Duchenne muscular dystrophy is caused by mutations in the dystrophin gene and several gene therapies are under investigation for correcting the mutations or replacing dystrophin.
Parkinson's Disease
Parkinson's disease is a neurodegenerative disorder that affects predominately dopaminergic neurons in the substantia nigra. Symptoms generally develop slowly over years and can include tremors, bradykinesia, limb rigidity and gait and balance problems.
There is no cure for Parkinson's disease and existing treatment options, including medications and surgery, are only symptomatic. A better understanding of the pathogenesis of the disease will enable the design of gene therapies for targeting aberrant pathways.
Huntington's Disease
Huntington disease is a progressive brain disorder that usually appears in a person's thirties or forties and begins with symptoms that include irritability, depression, small involuntary movements, poor coordination, and trouble learning new information or making decisions. Many people with Huntington disease develop involuntary jerking or twitching movements known as chorea, which become more pronounced as the disease progresses. Affected individuals may have trouble walking, speaking, and swallowing.
There is no cure for Huntington's disease and patients with this disorder usually live about 15 to 20 years after signs and symptoms begin.
Alzheimer's Disease
Alzheimer disease is a degenerative disorder of the brain that causes dementia and usually appears in people older than 65. As the disorder progresses, some patients with Alzheimer's disease experience personality and behavioral changes and have trouble interacting in a socially appropriate manner. Ultimately, in later stages of the disease, they require total care.
While some medications and management strategies may temporarily improve symptoms, there is no cure for Alzheimer's disease. Some forms of this disease have well known genetic causes and are potential targets for corrective gene therapies.
Amyotrophic Lateral Sclerosis
ALS is a progressive neurodegenerative diseases that affects nerve cells in the brain and spinal cord, causing loss of muscle control. ALS often begins with muscle twitching and weakness in a limb, or slurred speech. Eventually, ALS affects control of the muscles needed to move, speak, eat and breathe. There is no cure for this fatal disease but several gene therapies are under investigation to target the genes responsible for ALS.
RETT SYNDROME
Rett syndrome is a neurological disorder that occurs primarily in girls and leads to severe impairments, affecting nearly every aspect of the child’s life. Infants seem healthy during their first six months, but over time, rapidly lose coordination, speech, and use of the hands. There's no cure for Rett syndrome, but medications and physical therapy help manage symptoms and improve quality of life.
There are some well-characterized mutations that cause Rett syndrome and are promising candidates for gene correction therapies.
Devyani Swami Ph.D.
Postdoctoral Fellow
Department of Bioengineering
Michael Gapinske
Graduate Student
Department of Bioengineering
Jackson Winter
Graduate Student
Department of Bioengineering
Shraddha Shirguppe
Graduate Student
Department of Bioengineering
Angelo Miskalis
Graduate Student
Department of Bioengineering
Daphne Anand
Graduate Student
Department of Molecular and
Integrative Physiology
Nick Gosstola
Graduate Student
Department of Bioengineering
Daniel Nguyen
Graduate Student
Department of Bioengineering
Abhishek Bhattacharjee
Undergraduate Student
Department of Bioengineering
Collin Kao
Undergraduate Student
Department of Bioengineering
Gianna Elias
Undergraduate Student
Department of Bioengineering
Dana Joulani
Visiting scientist
Department of Bioengineering
Alexander Brown Ph.D.
Pankaj Achyara
Kate Love
Lauren Grant
Nathan Tague
Nikhil Shiva
Sony Manandhar
Peyton Muehlhauser
Anton Christensen
Eileen Johnson
Anna Busza
Micca Hecht
Kurt Kostan
Riley Lehmann
© 2015 Pablo Perez-Pinera.