Research

Neurodegenerative diseases are among the most pressing and devastating health challenges facing aging populations globally. With stem cells, we can now generate brain tissue in the lab from our patients. We utilize these patient-specific models to better understand the origin of these disease,  develop personalized treatments for them. 

The Khurana Lab is located within the Ann Romney Center for Neurologic Diseases at Brigham and Women’s Hospital and Harvard Medical School. Together with our local, national and international collaborators, we strive to better understand and develop therapies for some of the most detrimental age-related disorders of our time: neurodegenerative diseases.

CENTRAL PROBLEM:

Understandably, each patient diagnosed with a neurodegenerative disease has a burning question: “Why me?” We believe every patient deserves the answer to that question. Neurodegenerative diseases are heterogeneous. We believe that the same disease, for example Parkinson’s disease, can be triggered in different ways in different patients. This means that a “one size fits all strategy” may not work for therapy. Our lab aims to  develop methods to subtype our patients, to classify each one according to the specific trigger and answer that “Why me?” question. This understanding will ultimately enable us to develop personalized medicines: we will be able to appropriately match a patient to the right drug.

UNIQUE PATIENT POPULATIONS:

Thanks to the generosity of patients and their caregivers, we generate our genomes,  biomarkers, imaging and stem-cell data from patients that we know and care for. This allows us to ask questions related to the specific  patient being investigated, and enables our personalized medicine approach. In some cases, we search far and wide for the right patients to study. Patients with multiple system atrophy (MSA)  visit us nationally and internationally. We partner directly with patients harboring rare alpha-synuclein mutations.  For example, we closely work with a Spanish kindred in Northern Spain harboring the alpha-synuclein E46K mutation. For polyglutamine expansion disorders, we are developing gene therapies for specific patients with our collaborators and testing them in their matched stem-cell models.

DISEASE FOCUS:

The approaches we develop are readily applicable to all neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease. Our current projects focus on: 

BASIC RESEARCH QUESTIONS

While neurodegeneration may originate differently in different patients, there is one common denominator: each disease is defined by the abnormal accumulation of a particular protein. In Parkinson’s disease, for example, that protein is called alpha-synuclein. We focus on this “common denominator” of protein misfolding in the multitude of approaches we use:
How does protein misfolding perturb the physiology of and interaction between distinct cell types within the nervous system?
How does the physiologic function of proteins relate to the toxicity that results when these proteins misfold? We believe both “toxic gain” and “loss” of protein functions are central to neurodegeneration. We are actively testing how closely antisense oligonucleotide(ASO) therapies rescue primary pathologies.
Do distinct forms (or “strains”) of misfolded proteins cause pathology in different ways?
How do environmental and inflammatory factors contribute to protein misfolding and its consequences?
How can we best exploit our understanding of perturbed proteostasis for clinical translation – i) better personalized stem cell models; ii) better biomarkers; iii) patient-specific therapies

BASIC RESEARCH APPROACHES

“SYSTEMS CELL BIOLOGY” APPROACH: In induced pluripotent stem cells (iPSc) from patients with neurodegenerative disease we catalog all of the key interactions (genetic and physical) of these aggregation-prone proteins in different cells of the nervous system (Fig. 1). We use these “maps” to read our patient’s genomes for clues as to the origin of the disease in that patient. We factor in their environmental exposures, from toxicants in pesticides to microbes in their gut. Our Publications page lists our recent studies. Specific methods include:
Tissue engineering approaches, including reprogramming, genome editing and development of 2D and 3D CNS cultures. We are collaborating with the Studer lab (Sloan Kettering) to multiplex glio-neuronal co-cultures. In this way, we hope to capture CNS cells from whole cohorts of patients in a single “village” within a dish (Fig. 2).
Genetic and spatial mapping (Fig. 1) utilizing:
multiplexed CRISPR- or base editing-based screens
proximity (e.g. APEX2) labeling or yeast/membrane-2-hybrid protein-interaction mapping
computational tools that integrate these data
Statistical genetics and AI/ML genomics: (in collaboration with Drs Shamil Sunyaev, HMS Jian Peng, UIUC, we develop tools for rare genome-variant analysis of our patients.
Gene therapies: We are working with collaborators (including Dr Timothy Yu at Boston Children’s Hospital) to better understand gene knockdown approaches (e.g. antisense oligonucleotides). We “de-risk” these therapies in stem-cell models matched to patients. The aim is to better understand a therapy before it is introduced into the patient.

FIG. 1 The concept of genetic and spatial mapping of proteotoxicity (adapted from Jarosz and Khurana Cell 2017). A genetic map is a molecular network encompassing genes that impact a proteotoxicity when overexpressed or deleted. A spatial map comprises proteins that are in the immediate vicinity of a protein of interest. A schematic diagram of an integrated network is shown at right. Recently, such maps were generated for a-syn proteoxicity (a genetic map in yeast and a spatial map in neurons; Khurana et al., 2017; Chung et al., 2017), revealing a connection between this toxicity and 12 known parkinsonism genes. The significant overlap of genetic and spatial maps revealed an intimate relationship of a-syn toxicity to its functional interactions and location.

FIG. 2 Glio-neuronal co-cultures from entire  populations of patients will ultimately be captured in a single “village”, ushering in possibilities of clinical trials “in the dish. Molecular-level knowledge of protein misfoylding will guide identification and reversal of pathologic phenotypes in these villages. 

CLINICAL RESEARCH QUESTIONS & APPROACHES

APPROACH IN THE CLINIC: We aim to develop different approaches to clinical trials. We select certain patients for “deep phenotyping” – we follow their trajectory with clinical measurements, biometrics and biomarkers in the blood, spinal fluid and with brain imaging. With our collaborators in the Brigham and Women’s Movement Disorders Genetics Clinic, we obtain a whole-genome sequence. A skin biopsy enables us to develop a personalized stem-cell model from each patient.
PERSONALIZED STEM-CELL MODELS: From skin biopsies we, firstly, generate an induced pluripotent stem cell from the patient. This cell is an embryonic stem cell-like cell that enables us to generate neurons and other CNS cell types from our patients. Secondly, from skin (or spinal fluid or even a nasal brushing) we capture the toxic protein (alpha-synuclein, for example) that is aggregating in that specific patient. This allows us to create a truly personalized model from the patient – capturing the right cell type and the right form of the aggregating protein “in the dish” in our lab.
“n-of-few” CLINICAL TRIAL APPROACH: Ultimately our approach culminates in the introduction of a drug at the right time.  For patients we actively track in the clinic, we will have the prior clinical and biomarker “history” of the patient, enabling us to better understand the response to that drug. Testing the drug in a patient’s own brain cells in the lab before a clinical trial is attempted should increase our chances of success in the clinic.
GENE THERAPY: Gene therapies: We are working with collaborators to better understand gene knockdown approaches (e.g. antisense oligonucleotides). We “de-risk” these therapies in stem-cell models matched to patients. The aim is to better understand a therapy before it is introduced into the patient.

FUNDING

Among other funding sources, current funding is generously provided through federal grants (NIH R01, NIH R21, DOD), investigator-based awards to Vik Khurana (he is a New York Stem Cell Foundation Robertson Stem Cell Investigator and George Cotzias Fellow of the American Parkinson Disease Association), the Brigham Research Institute, the National Ataxia Foundation, the MSA Coalition, an Aligning Science Across Parkinson’s award, and through the Ken Griffin award of the Michael J. Fox Foundation.

RECENT SEMINARS & MEDIA

This “Parkinson’s Disease 101” seminar for the Harvard BrainScience Initiative provides an introductory primer to Parkinson’s disease and  touches on themes that relate to research in the lab.

In the following video for the American Parkinson’s Disease Association, and Harvard Gazette article,  Vik and team member Erinc Hallacli discuss new findings from the lab that link the Parkinson’s protein alpha-synuclein to mRNA and gene expression regulation, and the wider implications of these findings for understanding and treating Parkinson’s disease.

In this short video, team member Asia Korecka-Roet describes an ASO genetic therapy project she is leading for a young boy with DRPLA, a polyglutamine expansion-driven neurodegenerative disorder. In this project we are testing the gene therapy in stem-cells generated from the patient prior to clinical trial. The aim is to optimize the genetic treatment. This is a collaboration with Dr Timothy Yu at Boston Children’s Hospital.

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