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Applied Research

In principle it can be applied at various levels in an organism in order to develop a cure for a disease. Therefore, the disease must be understood as precisely as possible, and perhaps developed into a holistic therapy.

Starting points in the organism

Possible therapies


Nucleic acid

DNA and RNA based therapy


Gene therapy, Exon skipping, Read through



Protein based therapy


Protein replacement therapy, pharmacological chaperones

  Signaling pathway / metabolic

Modulation of signal transduction, immunomodulation


Small molecules,immunosuppressives



Replacement of destroyed cells


Cell replacement therapy, stem cell therapy


Combination therapy


Combination of different approaches


DNA and RNA based therapy

To combat the cause directly, it is ultimately necessary to correct the genetic defect on chromosome 16. This could be done using gene therapy. Intact DNA is brought into the cell, which then forms the basis for a functional protein. A distinction is made between the viral and non-viral gene therapy. Thus, for example, the intact gene by AAV vector (adeno-associated virus) is passed through into the cells with the rare disease "Lipoprotein Lipase Deficiency".

Other than the possibility of gene replacement, the approach of exon skipping and the read-throughs also exists. A defective gene segment in the transcription will be skipped in exon skipping, so a frameshift (such as those also present at NCL) can move around. Therefore, a slightly shortened, but possibly still intact, protein is formed. This method has already been intensively investigated for the treatment of Duchenne muscular dystrophy and could be used for NCL represent a promising approach. Another possibility mutates DNA to pass over, the method provides the read-throughs. Here, a stop codon is skipped, which is caused by a mutation. Thus, the transcription can continue normally. This treatment option is not applicable to all forms of NCL mutation. David Pearce is currently testing read-through drugs for a rare CLN3 mutation.


Therapy at the protein level

If proteins are no longer functional in the specific enzymes or even completely absent, the possibility to partially replace these exists. An enzyme replacement therapywould be feasible only in the infantile (CLN1), the congenital (CLN10) and in the late-infantile (CLN2) NCL because soluble lysosomal enzymes are affected. Input proteins must therefore be included only in the cell and not be incorporated into a lipid membrane - as in the juvenile NCL. In the juvenile NCL the CLN3 protein that is localised in the lysosomal membrane is missing. As yet there is no example that membrane proteins can be replaced, but this is the subject of current research. Many other lysosomal storage diseases, where soluble enzymes are affected, could already be treated by enzyme replacement therapy. This method is, for example, successfully applied in Gaucher disease.

Furthermore, there is the possibility of chaperone treatment. Chaperones are "folding helper" for proteins. In this way, defective enzymes in the cell can be reactivated. Chaperones are actually also proteins. In the context of therapy these are meant as pharmacological chaperones. These agents then mimic the function of the "natural" chaperones. For some lysosomal storage diseases, thechaperone therapy is in a clinical trial.


Modulation of signal transduction / Immunomodulation

There are several medications on the market that achieve promising results comparable to NCL diseases. The transduction of signals cannot be blocked or enhanced withsmall agents (small molecules) through modulation of receptors. The cell function can be changed and adjusted, thereby engaged in both the metabolism of the cell, as well as the metabolism of the organism. Most drugs apply this point. This could, for example, turn Memantine into a potential drug in the treatment of NCL. Memantine is currently used with neurodegenerative diseases such as Alzheimer's and Parkinson's. Memantine is an NMDA receptor antagonist. The NMDA receptor is a glutamate receptor in the central nervous system and plays an important role in learning and memory processes.

The initial promising results indicate that immunosuppression could potentially have a positive effect on disease progression in NCL. Apparently inflammatory phenomena in the brain contribute overall to the lysosomal storage diseases pathogenesis. Thomas Kühl and Janos Groh have figured this out in their doctoral thesis. So far, the positive effects were, however, shown only in the mouse subjects. A transfer to humans has yet to occur.


Therapy at the cellular level

In NCL, the nerve cells die. Replacing these cells is another conceivable therapeutic approach. Neural progenitor cells or stem cells could be injected into the brain and therefore compensate for the loss of nerve tissue. A cell replacement therapy also naturally brings along large obstacles. The company "StemCells Inc." even already led a clinical Phase I trial for the treatment of NCL using human, neuronal stem cells. However, a second study was provisionally cancelled due to there being too few subjects in 2011.


Combination therapy

Each of the different therapeutic approaches has to overcome certain obstacles and faces various limitations. Theultimate treatment of NCL is by necessity a combination of approaches. Therefore, for example, a possible option would be an immune modulation in conjunction with a genetic treatment. For this reason every single therapeutic approach needs to be researched furtherin order to find a way to defeat NCL.



This German - English translation was done by the translators Tizzy Mann, Andrea Murphy, Kate Humby and Marcia Neff for the PerMondo initiative that involves providing free translations for NGOs. PerMondo is sponsored and run by the translation agency Mondo Agit.