Batten Research Learning Lab: Therapeutic Strategies

What is Enzyme Replacement Therapy?

(From Guide to Symptomatic Treatment of Neuronal Ceroid Lipofuscinosis)

Enzyme infusion has been proven effective for other lysosomal storage diseases and in vitro trials have shown that the therapy is also effective in NCL. Animal trials using, inter alia, mouse models for LINCL, have found that the onset of symptoms is delayed, and the mice are living longer when the mice were infused with a small quantity of enzymes (Sleat et al., 2008). One of several challenges associated with this method is that enzymes have a hard time penetrating the brain due to the blood-brain barrier.

Therefore, it may be necessary to inject the enzyme to the cerebrospinal fluid, either directly into the lateral ventricles or by intrathecal injection (needle in the back). Other challenges include producing a “pure” enzyme, the body making antibodies against the enzyme, anaphylactic (allergic) reactions and tolerance development (the drug will, at one point, stop working). The enzyme must be injected regularly, which makes the therapy cost-prohibitive. ERT is only an option for the types of NCL where the affected enzyme is soluble (CLN1, 2, 5 and 10).

The Food and Drug Administration (FDA) recently approved the first enzyme replacement therapy in Batten disease. Brineura™ (cerliponase alfa) is approved to slow the loss of ability to walk or crawl (ambulation) in children with symptoms of CLN2 disease who are 3 years of age and older. Visit www.brineura.com  and contact Tracy Kirby at tkirby@bdsra.org for more information.

What is Gene Therapy?

Gene therapy is a treatment approach where we try to treat a genetic disease by physically putting the missing gene back into cells within a patient’s body. The way everyone is doing this with Batten disease, is we engineer a virus to do this. These are viruses that don’t replicate. Rather, they are basically a shell carrying the missing gene into cells in the body, kind of like a molecular delivery truck. Viruses do this really well, so we hijack them to work for us. Since we are delivering the DNA itself, we are correcting things on a genetic level. This makes it a fairly permanent fix after one injection. With Gene Therapy, you aren’t delivering the gene to every cell in the body. You are only delivering the gene to the cells that the virus goes to. We try to target the virus to what we can and what we think is most important, but that can still leave gaps. Thus, in the future, we need to fill those gaps with another treatment or make our gene therapy technology better (Dr. Gray, BDSRA 2017 Gene Therapy Basics)

Gene Therapy in Batten disease (From Guide to Symptomatic Treatment of Neuronal Ceroid Lipofuscinosis)

Gene therapies work in several different ways. One possibility is to harvest blood cells from the patient, correct the genetic cell defect in the laboratory by transplanting a new gene, and returning the cells to the patient. A modified virus is used as a vector to introduce the right gene into the blood cells. This is called ex vivo gene therapy. It is also possible to introduce a gene into the host cell in vivo. In vivo therapies make use of a virus with reduced virulence (a weakened virus) as a vector. This method has been tested in several animal models with varying results. Both intracranial injection and injections into the vitreous body of the eye have been tried. Central challenges include finding the right vector, and the right time to intervene. Two phase 1 clinical trials have been carried out on patients with CLN2. Both trials made use of adenoviruses as a vector. In both these trials, the vector carrying the CLN2 gene was injected into 12 different locations inside the brain. One study observed a delayed progression of the disease, but the disease did progress (Worgall et al., 2008). Currently, there are two ongoing clinical trials for CLN2 (ClinicalTrials.gov identifiers NTC01161576 and NCT01414985) and a trial for CLN6 (ClinicalTrials.gov identifier NCT02725580). The main purpose of these trials is to determine whether the method is safe and whether the patient can tolerate it. The secondary endpoint for the trials would be changes in brain atrophy and treatment efficacy.

What are therapies involving Small Molecules?

(From Guide to Symptomatic Treatment of Neuronal Ceroid Lipofuscinosis)

The idea behind this type of therapy is not to repair or replace the protein deficiency, but to enhance the patient’s remaining enzyme activity. This is done in an effort to restore cell function. One benefit of this type of treatment is that it is non-invasive, and it may one day be possible to develop medication to be taken orally. This type of therapy can be divided into various sub-categories:

Pharmacological “Chaperones”

This type of therapy is still highly experimental, but testing in cell culture models has shown promising results. The term “chaperone” can be defined as someone who accompanies and looks after another. In this context, the chaperones are small molecules stimulating enzymes with residual activity to function more normally. For example, some point mutations to NCL genes affect protein production, causing the protein to not fold properly.

However, the protein may have some residual enzyme activity if it can be modified by cell machinery and transported to where it needs to go. Cell control systems often degrade the protein before it has a chance to act. Pharmacological chaperones bind themselves to the protein, preventing degradation, allowing the protein to modify and start functioning.

Receptor Modulators

Receptor modulators are chemical compounds that bind themselves to receptors in the cell to increase, reduce or change the receptor’s activity. The AMPA receptor in the central nervous system is a receptor thought to be significant for NCL. Applying a mouse model, researchers have introduced a non-competitive AMPA antagonist with good results when administered early in the progression of the disease (Kovacs & Pearce, 2008).

Substrate Reduction Therapy (Removing NCL Deposits)

Clinical trials studied the effect of combining cysteamine bitartrate and N-acetylcysteine to treat INCL (ClinicalTrials.gov identifier NCT00028262). Unfortunately, this had no effect on the progression of the disease, even though the treatment succeeded in reducing the amount of storage material in peripheral leucocytes and parents reported less irritability and increased concentration (Levin et al., 2014).

Immunological modulators

As with all neurodegenerative diseases, NCL is characterized by an ongoing inflammation of the central nervous system. Researchers agree that persistent inflammation involving microglia and astrocytes contribute to the progression of the disease. Serum neuronal antibodies have been observed in patients with NCL (GAD65). Immunosuppression therapy could therefore potentially affect the progression of the disease. Positive effects of treatment with mycophenolate (Cellcept®) have been observed in mouse models (Seehafer et al., 2011), and in an ongoing clinical trial in the US, patients with Juvenile CLN3 are being treated with this immunosuppressing drug (ClinicalTrials.gov identifier NCT01399047).

Treatment with prednisolone has also been shown to temporarily improve motor function, but it had no significant therapeutic effect in terms of prognosis (L. Aberg et al., 2008).

What is Stem Cell Therapy (regenerative medicine)?

Stem cell therapy, also known as regenerative medicine, promotes the reparative response of diseased, dysfunctional or injured tissue using stem cells or their derivatives (Mayo Clinic, Stem Cell: What they are and what they do)

Stem Cell Therapies in Batten disease (From Guide to Symptomatic Treatment of Neuronal Ceroid Lipofuscinosis)

Theoretically, stem cell therapies work in one of two ways: either by the stem cells producing the missing enzyme, which can then be taken up by the enzyme deficient cells (cross-correction) or by the stem cell differentiating and replacing the person’s own (diseased) cells. There have been trials involving both hematopoietic stem cells (cells from blood or bone marrow) and neural stem cells (nerve cells). Both types have been used in animal models and clinical trials

Hematopoietic Stem Cells

Hematopoietic stem cell transplantation has been researched to treat INCL, but while enzyme activity normalized in the white blood cells, activity remained low inside the brain (cerebrospinal fluid). The therapy had minimal effects on diseases progression (Lonnqvist et al., 2001). Hematopoietic stem cell transplantation has also been found to be largely ineffective against LINCL and JNCL (Lake, Steward, Oakhill, Wilson, & Perham, 1997).

Neural Stem Cells

This method works by getting stem cells to differentiate into nerve cells (neurons or glia cells). Animal trials have shown that the therapy works primarily through “cross-correction”, and that the therapy was able to delay loss of motor functions. An open phase 1 trial on patients with INCL and LINCL proved that the method of transplanting neural stem cells directly into the brain’s cavities (lateral ventricles) with subsequent immuno-suppression was safe, but so far it has not been determined whether the therapy is effective (Selden et al., 2013). Post-mortem examinations of 3 patients found donor cells in 2 of them (Selden et al., 2013).

Additional Resources

https://globalgenes.org/toolkits/understanding-gene-therapy/introduction/

Sondhi, Dolan, Jonathan B. Rosenberg, Benjamin G. Van De Graaf, Stephen M. Kaminsky, and Ronald G. Crystal. “Advances in the treatment of neuronal ceroid lipofuscinosis.” Expert Opinion on Orphan Drugs 1, no. 12 (2013): 951-75.

Kohan, R., I. A. Cismondi, A. M. Oller-Ramirez, N. Guelbert, V. Tapia Anzolini, G. Alonso, S. E. Mole, R. Dodelson De Kremer, and I. Noher De Halac. “Therapeutic Approaches to the Challenge of Neuronal Ceroid Lipofuscinoses.” Current Pharmaceutical Biotechnology 12, no. 6 (2011): 867-83. doi:10.2174/138920111795542633.

Geraets, Ryan D., Seung Yon Koh, Michelle L. Hastings, Tammy Kielian, David A. Pearce, and Jill M. Weimer. “Moving towards effective therapeutic strategies for Neuronal Ceroid Lipofuscinosis.” Orphanet Journal of Rare Diseases 11, no. 1 (2016). doi:10.1186/s13023-016-0414-2.