NCL RESOURCE - A GATEWAY FOR BATTEN DISEASE

Treatment

The development of therapy for Batten disease is at a very early stage but is progressing. The ultimate aim is a complete cure for all types of Batten disease. Along the way to achieving this might be the development of treatment that halts or delays the progression of some types of the disease. Successful therapy needs to reach the cells in the brain that die during the disease process, a difficult feat since the brain is specially protected from external influences. What is not known is whether the disease will later manifest elsewhere in the body if effects in the brain are prevented or reduced. If so effective treatments for this systemic disease will also have to be developed.

Cell, mouse and larger animal models exist to test out new therapies as they are developed. A number of different approaches are being considered. The first successful therapies are likely to apply to those affected by mutations in CLN1, CLN2 or CTSD as these encode soluble enzymes.

Some early phase clinical trials have begun in small numbers of patients. Here is a summary table of Human Clinical Trials for NCL.

Gene therapy

This is a way to deliver a corrected copy of the faulty gene into the cells that need it to function efficiently and correctly. Usually a modified viral vector is used to infect cells. Routes for delivery for this type of treatment might be via injection into the brain, requiring brain surgery; via a shunt into the CSF, the fluid which bathes brain cells; and via the blood supply using vectors that infect cells lining blood vessels. This approach is most likely to be effective for NCLs caused by mutation in genes encoding enzymes, as cells containing the corrected copy of the gene may be able to make enzyme that can be released and taken up by other cells not able to make the enzyme. Trials in mouse models for CLN1 and CLN2 are underway and are promising, with improvements already made in vectors used for delivery of the genes. A recent and important finding is that very early therapy (ie presymptomatic) provides best results. A safety trial for therapy in 10 children with mutations in CLN2 using delivery by brain surgery is underway by Weill Cornell Medical College, USA. This is now expanded to include a new vector and 8 children who may be further along in their disease course.
Safety study of a gene transfer vector for children with Late Infantile Neuronal Ceroid Lipofuscinosis (Phase I).
Safety study of a gene transfer vector (Rh.10) for children with Late Infantile Neuronal Ceroid Lipofuscinosis
AAVRh.10 administered to children with late infantile neuronal ceroid lipofuscinosis with uncommon genotypes or moderate/severe impairment (Phase 1, 2)
Further safety trials using improved vectors in mouse and primate models are in progress. This approach is also being considered for juvenile CLN3 disease. This approach would be suitable for treatment that targeted only the retina in the eye.

Stem cell therapy

This approach delivers cells that can make the correct version of the faulty protein. These cells could either deliver the correct enzyme to other cells or might even replace cells that die during the disease process. Trials in a mouse model for CLN1 are underway. Clinical trials (Phase I) to test the safety and efficacy of this type of approach in a small number of children took place in 2006-2008 by StemCells Inc in the USA. Six children took part, two with INCL and four with LINCL. Cells were delivered using surgery. A long term follow-up of these children is now underway.
Study of the safety and preliminary effectiveness of human central nervous system (CNS) stem cells (HuCNS-SC) in patients with Infantile or Late Infantile Neuronal Ceroid Lipofuscinosis (NCL) (Phase I). A second trial planned to deliver cells to children much earlier in the disease was halted before recruitment began.
Safety and efficacy study of HuCNS-SC in subjects with Neuronal Ceroid Lipofuscinosis (Phase 1b).
Previous attempts at bone marrow transplants in patients (infantile, late infantile and juvenile) have not been successful even when performed prior to development of symptoms. This is probably because normal protein produced by the transplanted cells is unable to cross into the brain effectively. However this approach is still under consideration.
Stem cell transplant for inborn errors of metabolism (Phase II, Phase III)
Much work is needed before this approach can be considered a safe and effective treatment for NCL. For those considering this possibility, this site A closer look at stem cell treatments may provide some guidance on what to consider and what questions to ask any clinic suggesting this as a treatment for NCL. Certainly a clinic should provide published scientific literature on any procedure suggested. An experimental technique that is part of a scientific study/clinical trial should not result in a charge to families for taking part since expenses will be paid by those conducting the trial procedure.

Enzyme therapy

This approach delivers enzyme directly to the brain. Routes for delivery for this type of treatment might be via injection into the brain, requiring brain surgery; via a shunt into the CSF, the fluid which bathes brain cells; and via the blood supply, providing there is a way to transfer the enzyme across the blood-brain barrier. Trials in a mouse model for CLN2 showed that it is possible to deliver TPPI enzyme to the brain using the CSF.

A clinical trial showed that delivery of TPP1 enzyme into the brain is safe for children and a treatment for CLN2 disease, Brineura (Biomarin BMN-190 Cerliponase Alfa), is now approved by the EMA and FDA.

Biomarin Pharmaceutical worked with University Hamburg-Eppendorf, Germany; Great Ormond Street Hospital, UK; Bambino Gesu Children's Hospital, Rome. Safety and efficacy study of BMN190 for the treatment of CLN2 patients (Phase 1/2). A trial continues to test whether delivery of human TPP1 enzyme to children under the age of 2 years is safe and effective, and also follows those children already treated for at least 10 years as part of a long-term safety study. A Multicenter, Multi-national Open-label Program to Provide BMN 190 to Patients Diagnosed With CLN2 Disease. Biomarin Pharmaceutical continues to work with University Hamburg-Eppendorf, Germany; Great Ormond Street Hospital, UK; Bambino Gesu Children's Hospital, Rome; and Nationwide Children's Hospital, Columbus, Ohio, United States.

Drug therapy

As more is discovered about changes that occur in the brain in NCL patients there may be drugs that will ameliorate these effects. One such drug is EGIS-8332 which targets AMPA receptors and improved the performance of a CLN3 disease mouse model. Trials in humans have not yet started. Plans to test the drug talampanel (LY300164), which targets the same receptors and is used to treat seizures and Parkinson disease, in the mice are underway at the University of Rochester Medical Center in the USA.

Drugs that allow read-through of mutations that introduce premature stops in NCL proteins (especially PPT1 and TPPI) are being considered. Drugs that help a mutated protein to fold correctly and regain activity, perhaps by increasing the amount of a key chaperone such as Hsp70 that is available as well as other chaperones, are also under investigation. This approach is likely to be most suitable for proteins containing a missense mutation.

Immune therapy

The immune system seems to be affected, especially in juvenile NCL. Mice modelling juvenile NCL that cannot make antibodies seem to do better than those that can, as do mice treated with the immunosuppressant mycophenolate (mycophenolate mofetil, Cellcept, Myfortic, mycophenolate sodium or mycophenolic acid). A trial in juvenile CLN3 patients is underway.
Cellcept for Treatment of Juvenile Neuronal Ceroid Lipofuscinosis (JUMP)
Prednisolone given to juvenile patients in Finland reduced the occurrence of antibodies to GAD65 but there was no signficant effect on the disease course. Trials using other immunosuppressants to suppress the immune system in patients have not yet been started. Other possibilities include intravenous immunoglobulin (IVIG) which has been used in other immune-mediated diseases.

Storage material degradation

It may be that assisting cells to break down the accumulating storage material more efficiently would be beneficial. The drug cystagon (cysteamine) appears to help cells break down the storage material when cells are grown in the laboratory. This drug is also being tested in combination with Mucomyst which may help prevent cell death. Two trials are underway. Children with the classic form of infantile NCL have been treated and it appears that disease progression may be slowed but long term effects are not yet known. Another small group of children with milder forms of NCL caused by mutations in CLN1 have also been given the drug. The results of this trial are not yet known.
Cystagon to treat infantile neuronal ceroid lipofuscinosis (Phase II)

Inhibition of cell death

Work to identify the different mechanisms that may cause cell death in brain cells of patients is underway. One drug reported to inhibit cell death is flupirtine, also used as an analgesic. Some patients now take this drug but no clinical trial has taken place, so it is not yet possible to be sure that it works.

Assessment of therapy

In order to assess the success of any therapy the expected progression of all types of the disease needs to be fully known. Disease rating scales are currently being updated and expanded by several centres, and an International NCL patient Registry is in progress.
Genotype - phenotype correlations of LINCL
Clinical and neuropsychological investigations in Batten disease

Useful sites

UK Stem Cell Foundation