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.
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:
- synucleinopathies like Parkinson’s disease, multiple system atrophy and dementia with Lewy bodies
- cerebellar ataxias, from sporadic ataxias like multiple system atrophy, to hereditary ataxias like spinocerebellar ataxias, especially spinocerebellar ataxia type 3 (SCA-3) and dentatorubropallidoluysian atrophy (DRPLA).
“SYSTEMS CELL BIOLOGY” APPROACH IN THE LAB:
We generate induced pluripotent stem cells (iPSc) from patients with neurodegenerative disease to re-create the disease process “in a dish.” While the disease 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. In our “systems cell biology” approach we use cutting edge tools to catalog all of the key interactions of these aggregation-prone proteins in different cells of the nervous system. 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. Ultimately, we use human stem-cell models generated from our patients to test our hypothesis and to develop strategies for reversing the defects. Our Publications page lists our recent studies.
APPROACH IN THE CLINIC:
Just as important as our molecular and cellular work in the lab is our mission to develop different approaches to clinical trials. In the clinic, 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 that is aggregating in that specific patient. For example, in our patients with alpha-synucleinopathy like Parkinson’s disease or multiple system atrophy, we can capture and then amplify the aggregating protein alpha-synuclein. 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 those few patients that we are deeply following (“phenotyping”) 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. Our hope is that by testing the drug in a patient’s own brain cells in the lab before a clinical trial is attempted, we will have a better chance of matching the patient to the right drug. This is a paradigm we call an “n-of-few” clinical trial: a few patients, deeply followed in the lab and the clinic, are matched to an appropriate drug. We recently completed our first such clinical trial for multiple system atrophy. Our methodology for that trial was described here.
LONG-TERM GOAL:
Insights from our integrative genomics and stem-cells will enable us to match therapies to specific patients.
PROOF OF PRINCIPLE:
In 2013, we succeeded in identifying and reversing abnormalities in stem-cell derived neurons from Parkinson’s disease patients (Chung*, Khurana* et al. Science, 2013). Ultimately, this stem-cell platform led to the testing and developing of new classes of drugs from stearoyl-coA desaturase inhibitors to beta-2-adrenergic agonists (outlined in our Publications page) that are in clinical trial. However, we believe many drug trials have failed in prior clinical trials, not because the drugs were poor, but because they might not have been ideally matched to many of the trial participants. Our recent efforts in our lab and in the biotechnology industry are now intensely focused on developing approaches to better match therapeutics to individual patients.
LOCATION:
The Khurana lab is situated within the Ann Romney Center for Neurologic Disease and is part of the Harvard Stem Cell Institute.We are located in the spectacular Hale Building for Transformative Medicine (BTM) in the main Longwood Medical Area of Harvard Medical School. Hale-BTM houses both the research and the clinical program, a proximity that greatly facilitates our translational objectives. In April 2018, Vik was appointed Chief of the Division of Movement Disorders at Brigham and Women’s Hospital.
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.
Here is a short video by team member Asia Korecka-Roet describes an ASO genetic therapy project 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.
