Research Topics

Neuronal Ceroid Lipofuscinosis (NCL or Batten Disease)

The Neuronal Ceroid Lipofuscinoses (NCLs), often referred to as Batten disease, are inherited neurodegenerative disorders characterized by progressive loss of brain function. In the vast majority of cases, the first signs appear during childhood. Among these signs are seizures, progressive vision loss culminating in blindness, and loss cognitive function and muscle control. The childhood-onset forms of NCL are invariably fatal, with death occurring from less than 10 years of age to the 20s, depending on which form of the disease a child suffers from. NCL is almost always an autosomal recessively inherited disease. Neither parent of an affected child shows any signs of the disease, but there is a one-in-four chance that any additional children they have will be affected with NCL. There are many variant forms of NCL. Mutations responsible for different forms of this disease have been found to occur in at least 13 different genes.

With the assistance of our laboratory, BioMarin Pharmaceutical has developed the first effective therapy for inhibiting brain degeneration in one of the NCL forms (CLN2 disease). This treatment, a form of enzyme replacement therapy, is marketed as Brineura (Home – Brineura). Based on studies we performed using our dog CLN2 disease model (Intravitreal enzyme replacement inhibits progression of retinal degeneration in canine CLN2 neuronal ceroid lipofuscinosis – ScienceDirect  Intravitreal enzyme replacement inhibits progression of retinal degeneration in canine CLN2 neuronal ceroid lipofuscinosis – ScienceDirect), a clinical trial is under way to determine whether a variation of this treatment can also inhibit retinal degeneration in children with CLN2 disease (Intravitreal ERT to Prevent Retinal Disease Progression in Children With CLN2 – Full Text View – ClinicalTrials.gov). We are conducting research to develop alternative treatments for CLN2 disease as well as treatments for other forms of NCL. Using our dog model of CLN2 disease, we have found that gene therapy has the potential for preventing degeneration of both the brain and the retina (AAV gene transfer delays disease onset in a TPP1-deficient canine model of the late infantile form of Batten disease – PMC (nih.gov) Intravitreal gene therapy preserves retinal function in a canine model of CLN2 neuronal ceroid lipofuscinosis – ScienceDirect.  These approaches to treatment may be evaluated in children in the future.

NCLs occur not only in humans, but also in other species including dogs. NCLs have been reported in numerous dog breeds (see below). The mutations responsible for canine NCL have been identified in Dachshunds (two different forms of NCL), English Setters, American Bulldogs, Border Collies, Tibetan Terriers, Australian Shepherds (two different forms of NCL), Chinese Cresteds, Golden Retrievers, Australian Cattle Dogs, and Chihuahuas. We offer DNA tests for most of these mutations. We are interested in evaluating dogs of any breed that are suspected of suffering from NCL. Please contact us if you have a dog that is exhibiting signs consistent with NCL (tremors, visual impairment, cognitive decline, loss of coordination, changes in personality). We are testing gene and enzyme replacement therapies in dogs to evaluate the potential of these approaches for curing the human NCLs.

If you would like to contribute to our efforts to find cures for the NCLs, you can do so through the University donation portal. At that site you will find a “Please select a fund” drop-down menu. If you would like to donate to developing cures for children with NCL please select the “Batten Disease Research” option. If you would like to donate to our efforts toward finding the genetic causes of NCL in dogs, please select the “Canine Disease Research” option. After selecting the fund, please follow the instructions for making your donation. We will acknowledge any donations that are made for these studies.

Mutation Discovery for Inherited Neurological and Eye Diseases in Dogs and Domestic Cats

Our laboratory conducts research to identify mutations that are responsible for inherited diseases of the nervous system in dogs. Once we identify the disease-causing mutations, we develop DNA tests that we offer to dog owners so that they can determine whether their dogs harbor these mutations. These tests can be used by breeders to select dogs for mating such that the generation of affected puppies can be avoided. Discovery of the mutations responsible for the canine disorders also enables us to determine which human disease the dog disorder corresponds to. Affected dogs can then be used to help us in gaining a better understanding of the mechanisms involved in the disease processes and to test potential therapies for the disorders.

In addition to our research on inherited neurodegenerative disorders, we also investigate the genetic bases of some non-neurological diseases in dogs.  Among these is a connective tissue disorder that corresponds to human Ehlers-Danlos syndrome.  We have found that canine forms of this disease are associated with mutations in the ADAMTS2 gene. Homozygous ADAMTS2 Variants and Associated Disease Phenotypes in Dogs with Dermatosparactic Ehlers–Danlos Syndrome.

Below is a list of canine disorders for which we have identified the causative mutations.

We have also conducted research to identify the genetic bases of hereditary neurological diseases in domestic cats. Below is a list of feline disorders for which we have identified the causative mutations.

For information on requesting DNA tests for the canine diseases, please go to http://www.caninegeneticdiseases.net/.

Neurophysiology in Retinal Degenerative Diseases

A leading cause of serious visual impairment among the elderly is a disorder known as age-related macular degeneration (ARMD). The NDRL has conducted research to identify the cellular and molecular mechanisms that might underlie ARMD so that we might develop rational approaches to treatment and prevention. The primary risk factor for ARMD is, as the name implies, aging. We have therefore investigated normal age-related changes in retinal tissues that might contribute to the development of ARMD. A single layer of cells at the back the eye called the retinal pigment epithelium (RPE) performs a number of functions that are critical to maintaining the survival and function of retinal photoreceptor cells that convert light input into neurological signals. Age-related changes in the RPE may underlie the degeneration of photoreceptor cells that occurs in ARMD. We have therefore conducted studies to characterize age-related changes in the RPE. One of the most pronounced of these changes is the accumulation of autofluorescent lysosomal storage material (see the fluorescence micrograph below). The accumulation of this material, known as lipofuscin, may interfere with important RPE functions. We have found that lipofuscin is formed by chemical reactions between components of the photoreceptor cells, particularly derivatives of vitamin A. We have also found that impaired protection against nonenzymatic oxidation reactions promotes RPE lipofuscin accumulation. If we can develop methods to prevent these deleterious chemical reactions, we may be able to prevent the development of ARMD.

Understanding Neurodegeneration in Canine Degenerative Myelopathy (DM) and Human Amyotrophic lateral sclerosis (ALS)

In collaboration with Dr. Joan Coates, the NDRL is conducting research on amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s Disease. ALS is an adult-onset disorder that involves degeneration of the portions of the nervous system involved in muscle control. People who suffer from ALS undergo a progressive loss of muscle function because of degenerative changes in the nerves that control the muscles and in the muscles themselves.

This loss of muscle function eventually leads to paralysis and is ultimately fatal when the muscles involved in swallowing and breathing no longer function. There are currently no effective treatments for ALS. Some forms of ALS are caused by mutations in a gene known as SOD1, which directs synthesis of the enzyme superoxide dismutase. In people that have SOD1 mutations, large amounts of the superoxide dismutase protein accumulate in nerve cells involved in muscle control. This abnormal protein accumulation is accompanied by impaired ability of the nerves to communicate with muscles. An inherited disease very similar to ALS occurs in many dog breeds. The canine disease is called degenerative myelopathy (DM). Like some forms of ALS, we discovered that DM results from mutations in the SOD1 gene accompanied by accumulation of aggregates of superoxide dismutase protein in nerve cells of the spinal cord. We believe that by studying the mechanisms that underlie the disease pathology in DM, we can gain insight into the reasons people with ALS lose muscle function. This will aide in the development of rational approaches for treating ALS.

Our studies on DM require the analysis of nerve and muscle tissues from dogs that are euthanized as a result of the disease. We also analyze the same tissues from unaffected dogs that have been euthanized for other reasons. Our current focus is on Boxers and Pembroke Welsh Corgis, breeds in which the disease is fairly common. If you own a dog from one of these breeds that is older than 8 years and is going to be euthanized as a result of DM or for some other reason and you are willing to donate tissue samples, please contact Dr. Coates.