Research for Batten Disease/LINCL
Within the Federal Government, the focal point for research on Batten Disease and other neurogenetic disorders is the National Institute of Neurological Disorders and Stroke (NINDS). The NINDS, a part of the National Institutes of Health (NIH), is responsible for supporting and conducting research on the brain and central nervous system. The Batten Disease Support and Research Association and the Children’s Brain Diseases Foundation also provide financial assistance for research.
Next to that, there are several smaller organizations, like ours, that fund research in this field.
Batten disease / LINCL is an “orphan” disease (meaning it affects so few people and therefore, provides little incentive for drug companies to invest in research). Fortunately, there are some research laboratories (often affiliated with universities) focusing on research that will hopefully lead to a cure for this disease. There are also a larger number of scientists involved in research that concerns other lysosomal storage diseases. Their results might prove promising for Batten disease / LINCL as well.
In the last 20 years, we have learned a great deal about the genetic defect that causes Batten disease / LINCL. These genetic discoveries have enabled greater progress in the quest to find a treatment and a cure.
In September 1997, scientists at the Robert Woos Johnson Medical School and the Institute for Basic Research, in NY, announced the identification of the gene for the Late Infantile form of Batten Disease/NCL. The gene, CLN2, is located on chromosome 11.
Identification of the specific genes for Late Infantile, as well as Infantile, Variant Late Infantile and Juvenile Batten Disease/NCL has led to the development of DNA diagnostics, carrier and prenatal tests.
Scientists have discovered that the Late Infantile form of the disease involves a missing key lysosomal enzyme; Tripeptidyl Peptidase 1 (TPP1). This is a protease that becomes active within the lysosomes (as a result of interaction with other material) and starts to degrade the proteins. In other words, by degrading these proteins, it works to clean waste from the brain. Without this enzyme, the cells get clogged up and die.
Knowledge of the specific enzyme that is missing is now leading to the development of ERT (Enzyme Replacement Therapy), gene therapies, and stem cell therapy. In addition, there are certain drugs that seem to help in slowing down the progression of the disease.
ERT; Enzyme Replacement Therapy
ERT involves the manufacturing of the missing lysosomal enzyme outside of the body (in a bioreactor) which is subsequently administered to the patient. This has already worked very well for a number of lysosomal storage diseases like Gaucher, Pompe, and Fabry disease. The company, Genzyme (http://www.genzyme.com/) specializes in enzyme replacement therapy for lysosomal storage diseases.
So far, this has not been successful for LINCL. The main reason is that it has been very difficult to apply this therapy to the Central Nervous System (CNS) because of the Blood Brain Barrier (BBB) that stops the enzyme in an attempt to protect the brain from possible hostile material. LINCL predominantly manifests itself in the CNS so, this barrier results in a major hurdle to applying ERT for the CNS related lysosomal storage diseases, such as LINCL. Currently, research is being done to try to circumvent the BBB to get the enzymes into the CNS. One major advantage is the fact that the TPP1 enzyme is harmless outside of the lysosomes and can move freely between all the brain cells without causing any damage. Therefore, there is very little concern about getting the enzyme to other places while trying to reach the intended areas.
Gene Transfer Therapy
A very promising gene therapy trial under Ronald Crystal at Weill Medical College of Cornell University in New York, was started in June 2004. The trial was done with a small number of children and was funded by a number of families that worked together under the foundation of Nathan’s Battle. Six little holes were drilled into the brains of these children and then, a virus was injected into their brains via these holes. This virus, the Adeno-Associated virus (AAV2) has characteristics that makes it suitable to transport genetic information. Therefore, it is ideal for gene therapy.
Essentially, they employed a procedure that involved injecting an enzyme producing gene (CLN2) into the brains of Batten diseased children by means of this AAV2 vector. The first phase of this trial showed significant slowing of the disease’s progression during the 18 month follow up. However, at best, this therapy stops (or significantly slows down) the progression, it does not reverse the symptoms. Hence, whatever functioning had already been lost for the child, remained lost.
This therapy is currently the most hopeful, especially with children for whom the disease has not progressed too much. Moreover, a much more potent version of the AAV has been developed for an upcoming trial (at Weill Cornell), meaning that a much larger area of the brain will be covered with the correct gene.
In addition to the distribution methodology that Cornell uses (6 little holes at different places in the brain), there are also other means being tried to get the correct CLN2 gene delivered in the CNS. Convection Enhanced Delivery (CED) is another delivery mechanism. Recently, Beverly Davidson at the University of Iowa has also published a paper on this type of research that looks very promising. The likelihood is that this sort of therapy will eventually resolve most of the issues around this disease.
Stem cell Therapy
With stem cell therapy, cells with the correct CLN2 gene are added to the existing cells. These new cells produce the missing enzyme TPP1 and can also produce TTP1 for the surrounding cells (as the enzyme can float freely around between cells).
The company StemCells Inc. from California (http://www.stemcellsinc.com/) is working on treating lysosomal storage diseases by means of stem cell therapy. Recently a Phase 1 trial for LINCL was successfully conducted. In this trial doses up to 1 billion cells were administered without significant complications.
There are also clinics in China that offer stem cell therapy for Batten disease. A number of parents with NCL kids opt for this therapy (since there is no alternative treatment available) and spend 5 to 6 weeks in Beijing receiving 4 or 5 stem cell injections through the spinal cord fluid. This venue is generally not recommended by doctors in the US as there is a lack of transparency about the exact treatment protocols.The Chinese clinics do not claim that they can cure the disease but they believe this therapy may slow down the progression of the disease and reverse some of the damage. For further info please look at http:/www/stemcellschina.com
Drugs
In 2001 it was reported that a drug named Cystagon, to treat cystinosis (another rare genetic disease), may be useful in treating the infantile form of NCL. Preliminary results report that the drug clears away storage material from the white blood cells and also slows down the rapid neurodegeneration of infantile NCL.
Currently there are two drug trials underway for infantile Batten disease/NCL. Both trials are using the drug Cystagon. For additional information regarding this trial, contact the Batten Disease Support and Research Association (http://www.bdsra.org/).
Flupertine is a painkiller available in several European countries (but not in the US). It has been suggested by several experts that it should possibly slow down the progress of NCL, particularly in the Juvenile and late infantile forms. No trial has been officially supported in this venue, however.
JasperAgainstBatten project for repurposing of drugs
It has often been demonstrated that a drug that has been developed for disease A also happens to work for disease B. An example is that many drugs that have been developed to treat migraines are also effective in treating epilepsy.
JasperAgainstBatten is now developing an exciting partnership with the government to find new clinical applications for already-approved drugs. We will be screening over 3000 different already approved drugs in the government database to find potential beneficial effects that could also slow down the progression of LINCL. For instance, if an existing drug also helps to enhance the too little TTP1 that might exist in a Batten afflicted child (the residual TTP1), this would provide an instant treatment for children with this disease (since the drug in question already would have been proven safe).
These screenings will be done in a pilot partnership with the National Institutes of Health (NIH) and the parameters will be established by a scientific board comprising leading doctors and researchers. Already, we have 11 experts in childhood rare, fatal diseases onboard to do assays on these drugs. Our partner, Partnership for Cures will organize and coordinate the venture.
Miscellaneous
In addition, the seizures, that are symptomatic of this disease, can be (partly) controlled by standard AED (Anti Epilepsy Drugs). Intensive therapy (speech therapy, physical therapy and occupational therapy) can also be helpful in maintaining some skills as long as possible.
In conclusion, it appears that we are pretty close to a number of effective treatment methods for this heartbreaking disease that could, at the very least, slow down the progression significantly. Many of these experimental approaches cannot proceed without your help and funding.