1. Introduction
The Neuronal Ceroid Lipofuscinoses (NCLs; Batten disease) are a group of rare inherited fatal diseases that are characterized by the buildup of autofluorescent lipopigments in lysosomes [Citation1]. These diseases share clinical features of vision loss, epilepsy, dementia, and motor dysfunction. Many individuals with NCLs also experience behavior problems, sleep disturbances, and feeding/swallowing dysfunction. Each NCL has a characteristic pattern of onset, characteristic symptom manifestations, age-at-onset, and rate of progression [Citation1]. Current management for most forms of NCL is limited to symptom management [Citation1].
NCL forms differ by the causative gene, gene product, and affected the biologic process. Some of the affected proteins are soluble enzymes and others are membrane-bound proteins. There are no blood biomarkers that have been shown to correlate with disease progression in any form of NCL. Successful disease-modifying therapy (DMT) approaches may differ based on the location and function of the individual protein. For example, CLN2 disease is caused by a mutation in the gene that codes for tripeptidyl peptidase 1 (TPP1), a soluble lysosomal enzyme, which can be treated with enzyme replacement therapy (ERT). By contrast, CLN3 disease is caused by a mutation that affects a transmembrane protein and thus is not a candidate for ERT. Potential approaches to disease modification include, but are not limited to, small-molecule drugs, large-molecule drugs, genetic medicines, and combination therapies. There is currently one disease-modifying ERT (cerliponase alfa) that has been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for treatment of CLN2 disease. Several other potential disease-modifying therapies have been tested in small clinical studies (), but none of these has led to FDA or EMA approval. The focus of this editorial is on the current therapeutic pipeline for DMTs in the NCLs, including promising pre-clinical studies and planned and ongoing clinical trials. For a more extensive review, see [Citation2].
2. Small-molecule drugs
Pre-clinical approaches to small-molecule drug treatment for the NCLs have included strategies to improve lysosomal health or modulate autophagy, methods to improve transcription or protein production, and immunomodulation [Citation2]
2.1. Pre-clinical studies
2.1.1. Trehalose
Trehalose is a disaccharide composed of two glucose molecules. Studies have shown that trehalose, an activator of Transcription-Factor EB (TFEB), reduces the buildup of lipofuscin in both cell and mouse models [Citation6]. The enzyme trehalase lyses trehalose in the small intestine, so one barrier to using trehalose therapeutically is that it cannot be administered enterally. Pre-clinical studies are being conducted to evaluate intravenous delivery of trehalose along with oral delivery of miglustat which inhibits trehalase [Citation7]. Beyond Batten Disease Foundation (https://beyondbatten.org/research/bbdf101/, 7/12/2020) and Theranexus Inc (https://www.theranexus.com/en/platform-and-products/drug-candidates.html, 7/12/2020) have partnered to develop a clinical trial of trehalose in combination with miglustat (BBDF-101) for CLN3 disease.
2.1.2. PPARα agonists
Peroxisome proliferator-activated receptor – alpha (PPARα) agonists have been shown to induce autophagy, which is thought to be impaired in many forms of NCL. Pre-clinical CLN2−/- mouse model studies of gemfibrozil (an FDA approved PPARα agonist used to regulate cholesterol) found decreased cellular accumulation of lipofuscin, increased motor coordination, and increased longevity [Citation8]. Polaryx Therapeutics has recently received Investigational New Drug (IND) approval from the FDA to test a PPARα agonist in CLN2 and CLN3 diseases (www.polaryx.com, 7/29/2020), to determine safety and efficacy.
2.2. Clinical studies
There are no currently enrolling clinical trials for small-molecule drugs in the NCLs. There is a recently reported n-of-1 trial of an antisense oligonucleotide (ASO) in CLN7 disease [Citation9]. ASOs act by facilitating skipping of a mutated portion of the gene to allow expression of a functional gene product, and thus is both small-molecule and genetic medicine. In the trial, a patient with a novel intronic mutation in the CLN7 gene was treated with an ASO called milasen. After the initiation of therapy with milasen, the child experienced a reduction in the frequency and duration of seizures. It is too soon to determine whether this therapy will alter the disease natural history. ASO therapies have been suggested as possible treatment for specific mutations in other NCLs [Citation2].
3. Large-molecule drugs
The primary large-molecule approach to DMT for specific forms of NCL has been enzyme replacement. This is only pertinent to those NCL forms that are due to impaired soluble enzyme function (CLN1, CLN2, CLN10, and CLN13). ERT for NCLs introduces recombinant enzymes into the central nervous system to replace the nonfunctional enzyme. Large-molecules, such as enzymes, do not cross the blood-brain barrier and therefore must be administered directly into the brain parenchyma or cerebrospinal fluid.
3.1. Pre-clinical studies
CLN1 disease is caused by a mutation in CLN1 resulting in a nonfunctional palmitoyl-protein thioesterase-1 (PPT1) enzyme. Pre-clinical mouse data showed that intrathecal administration of recombinant PPT1 enzyme reduced the amount of storage material and had a significant effect on lifespan and motor function in CLN1−/- mice [Citation10]. Collaborations Pharmaceuticals (https://www.collaborationspharma.com/pipeline, 7/13/2020) is developing a clinical trial for ERT in CLN1 disease.
3.2. Clinical trials
Cerliponase alfa (recombinant Tripeptidyl-peptidase 1; TPP1) was approved for use in CLN2 disease based on efficacy data from a phase I/II clinical trial that showed a decreased rate of decline, but not improvement, on the motor/language score of the Hamburg Rating Scale [Citation11]. There is an ongoing extension study evaluating the long-term effects of this treatment in children with CLN2 disease (NCT02485899). This therapy requires bi-weekly infusion through an implanted intracerebroventricular reservoir, and thus requires families to reside close to an infusion center.
4. Genetic medicines
There are no currently approved genetic medicines for the treatment of any NCL, but there are currently numerous gene replacement products in development and early testing phases. The prevalent approach is to use adeno-associated viruses (AAV) as the gene vector, most using AAV9, which is neuronotropic [Citation12]. The specific vectors, gene products, doses, routes of administration, and targeted populations are likely to vary across studies. The ultimate goal of gene therapy in NCLs is to introduce a functional gene into a sufficiently large number of neurons to prevent neurodegeneration. To be effective, the vector must be able to cross the blood-brain barrier or be delivered into the central nervous system. However, because the retina is also affected in the NCLs, direct delivery of gene therapy to the eye may be required to prevent vision loss. It also may require a different vector than that used in targeting the central nervous system. In addition, although NCLs are primarily viewed as disease of the nervous system, other organ systems may be impacted [Citation13,Citation14]. Consideration of how to direct treatments to those systems will ultimately be important.
4.1. Pre-clinical studies
Pre-clinical work on gene therapy in various NCLs has shown promising gene expression and impact on phenotype models in both small and large animal models [Citation15–17]. Several of these pre-clinical studies have led to planned or early phase clinical trials ().
Table 2. Current gene replacement therapy studies
4.2. Clinical trials
There are currently three gene therapy programs with IND approval ().
5. Combination therapies
Each of the individual approaches described above has shown promise in pre-clinical work. However, it is possible that a combination of two or more approaches will be more effective than any single approach. Potential combinations range from targeting both the brain and spinal cord with gene replacement therapy [Citation18], to combining enzyme replacement with gene replacement therapy or small-molecule therapy, to combining one of these approaches with another modality such as immune suppression or cell-based therapy [Citation19]. Combination of gene replacement with ASO therapy has been used successfully in children with spinal muscular atrophy [Citation20].
6. Conclusion
The NCLs are a group of rare fatal neurodegenerative diseases. Most NCLs do not have approved disease-modifying therapies. There are currently several therapies in varying phases of development including small-molecules, large-molecules, and genetic medicines. It is likely that a combination of multiple therapeutic approaches may be necessary to provide optimal benefit.
7. Expert opinion
The therapeutic horizon for the NCLs is expanding. Multiple approaches have shown promise in pre-clinical studies. Currently, there is equipoise regarding the best methods of modifying these diseases. Because the NCLs represent multiple distinct pathobiological processes, it is likely that any single therapeutic approach will not be definitive for all forms. Thus, it is important that work continues across the spectrum from small-molecule to large-molecule to gene therapy and beyond. Within the next two years, there will likely be multiple clinical trials across the NCLs. At the present time, the gene therapy pipeline is most promising because of the number of trials being planned and because it has the best potential to correct the underlying problem. Ultimately, based on complementary mechanisms of action, combination therapy may provide the best chance for meaningful disease modification.
The expanding pipeline presents unique challenges for this group of rare diseases. These are rare to ultra-rare diseases, and therefore, the number of potential participants in clinical trials is extremely limited. Ultimately, this may require the NCL patient and family community to choose among different treatment modalities or trial designs. In addition, the rarity presents challenges to designing appropriately powered trials. In the trial leading to the recent approval of cerliponase alfa, the effect size was substantial, and thus approval was based on a relatively small number of enrolled participants. If current therapies in the pipeline have similar magnitude effects, then large samples may not be needed. However, it is likely that some of these potential therapies will have smaller effects yet still provide meaningful disease modification. Demonstrating efficacy in those cases may require novel trial design or multi-national and multi-center collaboration.
Despite these challenges, there has never been more reason for optimism that consequential therapies for the NCLs are within reach.
Declaration of Interests
JW Mink and EF Augustine have acted as consultants to Neurogene Inc., Amicus Therapeutics Inc., Beyond Batten Disease Foundation, REGENEXBIO Inc., Polaryx Therapeutics Inc., and Abeona Therapeutics Inc. JW Mink and EF Augustine have also received grants from the BDSRA and NIH. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer Disclosures
Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.
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References
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