of NCL.
As of today, there is no treatment for the disease or way to reverse its symptoms, which include seizures, loss of vision, progressive loss of motor skills and sight, and mental impairment. Sometimes anticonvulsants help reduce seizures, and physical therapy allows patients to retain some motor functions, but in the long term, children afflicted with Batten disease become blind, suffer from dementia, and end up confined to bed. The only hope for a successful treatment might well reside in the use of stem cell therapy based on genetic (DNA) testing, enzyme assay, or both.
Although stem cell research is nowadays still controversial in the United States, it is steadily gaining greater support from the research community and regulatory bodies, including the Food and Drug Administration (FDA), especially for diseases that are not related to spinal cord injuries, such as Batten disease. Understanding Batten disease and knowing which clinical trials are currently under way is very important for the development of diagnostic procedures as well as therapeutic applications in neurological medicine.
Pathology of Batten Disease
Batten disease is essentially characterized by four types of NCL. Three begin in childhood, and a very rare one in adulthood. Congenital NCL is the most severe form of NCL. Soon after birth, affected babies develop respiratory failure, muscle rigidity, and extended episodes of seizures. Newborns with congenital NCL have abnormally small heads (microcephaly) and underdeveloped brains, with a loss of brain cells in areas that control thinking, emotions (cerebellum), and movement coordination (cerebral cortex). Affected infants also suffer from a deficiency of myelin, a fatty substance that protects nerve cells and promotes effective transmission of nerve impulses. Infants with congenital NCL die in a matter of hours or weeks after birth.
The rare, but fatal neurodegenerative disorder Batten disease has an autosomal recessive pattern of inheritance. In children, it is only inherited as an autosomal recessive trait. In adults, the inheritance pattern is still autosomally recessive but there is also a chance of it being inherited in an autosomal dominant fashion. (Wikimedia Commons)
Infantile NCL is found in children aged 6 months to 2 years. Like newborns, affected children have microcephaly and exhibit a short stature. They suffer from myoclonic jerks (sharp muscle contractions) and usually die before age 5, although some survive past that age but remain in a vegetative state for the subsequent years. Late infantile NCL begins in children between ages 2 and 4 and affects the nervous system. The typical symptoms usually are vision impairment, loss of muscle coordination (ataxia), and recurring seizures (epilepsy) that do not respond to drugs, translating in affected motor skills, a reduction of intellectual capacity, and behavioral issues. Children with this form of the disease often find themselves in a wheelchair by late childhood and most often do not survive past the first years into adolescence.
Adult NCL usually starts before age 40, with symptoms including seizures, movement disorders, impaired speech, and dementia. Unlike other forms of NCL, the adult form does not cause blindness and exists under two classifications: type A, inherited in an autosomal recessive pattern caused by mutations in the CLN6 gene; and type B, inherited in an autosomal dominant pattern caused by mutations in the DNAJC5 gene.
Current Clinical Trials in the United States
For more than a century, researchers have been investigating the mechanism and causes of Batten disease. Before 1995, the year that the CLN3 gene was deemed responsible for the disease, progress was very slow. However, the 1990s witnessed an acceleration in the development of new molecular biology techniques.
Today, the biochemical deficiencies that underlie several NCLs are being discovered: an enzyme by the name of palmitoyl-protein thioesterase has been proven to be inactive in the infantile (CLN1) form of Batten disease. In the late infantile form (CLN2), research proves that an acid protease, an enzyme hydrolyzing proteins, is the cause of this condition. In juvenile Batten disease (CLN3), a mutation on a gene has been identified as the culprit, but researchers are still trying to find the protein encoded by this specific gene.
In 2011, the first controlled clinical trial for the treatment of Batten disease was conducted by the University of Rochester. The trial included 30 patients who were experiencing symptoms of the disease, and aimed primarily at slowing its progression.
In November 2013, Weill Medical College of Cornell University conducted a nonrandomized safety and efficacy trial aimed at recruiting participants for a safety study of a transfer vector for a gene related to the disease.
In March 2014, the University of Rochester Batten Center (URBC) started to recruit participants for an eight-week trial on ambulatory children scheduled to receive an immunosuppressant (mycophenolic acid) used extensively in transplant medicine. The research center has developed the tools and processes to screen for the major mutation associated with juvenile Batten disease, as well as less common mutations in CLN3, PPT1 (CLN1), and TPP1 (CLN2) genes.
During summer 2014, the first controlled clinical trial for juvenile Batten disease will be launched by researchers at URBC. This has been made possible thanks to a $1 million grant from the Batten Disease Support and Research Association (BDSRA) and the FDA. The purpose of this endorsement is to ensure the safety of an FDA-approved drug (mycophenolate mofetil) aimed at slowing down or arresting the progression of the disease.
As a part of this trial, Jonathan Mink, MD, PhD, medical director of the Batten Disease Diagnostic and Clinical Research Center and chief of Child Neurology at URMC said in a statement that sheds light on the challenges ahead, “This isn’t heart disease or diabetes, with many affected people willing to help with clinical trials and investigative efforts. The sample size is miniscule, comparatively, and shrinks further when you consider that patients are exceedingly fragile.”
Other issues involved in carrying out such trials are partial understanding of the causes of the disease, a need to better predict outcome metrics intended to quantify the disease, financial limitations in collecting funds necessary to put a trial together, and difficulties in enrolling participants to take part in these trials. To overcome these hurdles in the future, a tight collaboration between all parties involved in research initiatives will be required, and a new generation of clinicians and research teams will need to be put in place to leverage all current resources for the benefit of patients.
Three research trials in Batten disease are currently enrolling participants in the United States for juvenile NCL and late infantile CLN2 diseases: the University of Rochester Batten Center in Rochester, New York; the Department of Genetic Medicine at Weill Cornell Medical College in New York City; and BioMarin, a pharmaceutical company based in California.
Morenike Trenou
Independent Scholar
See Also: Clinical Trials, Ethics of; Clinical Trials Outside the United States; Weill Cornell Medical College;
Further Readings
Boustany, R.-M. “Seizures, Depression and Dementia in Teenagers With Batten Disease.” Journal of Inherited Metabolic Disease, v.16 (1993).
Hofmann, S. L., A. Atashband, S. K. Cho, A. K. Das, P. Gupta, and J. Y. Lu. “Neuronal Ceroid Lipofuscinoses Caused by Defects in Soluble Lysosomal Enzymes (CLN1 and CLN2).” Current Molecular Medicine, v.2/5 (2002).
Clinical Trials, U.S.: Blood Deficiencies
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