Genetic Treatments for Rare Neurodegenerative Disorders

Abstract

Rare neurodegenerative disorders encompass a diverse group of conditions characterized by the progressive degeneration of the nervous system. Usually, a combination of genetic, biochemical, and clinical features characterizes these disorders. An overview, classification, and investigation of the genetic mutations and variants linked to rare neurodegenerative diseases are included in this chapter on genetic therapy for these diseases. The article discusses novel approaches to treating genetic illnesses, including gene therapy, CRISPR-based interventions, and RNA-based therapeutics. It includes case studies and particular instances of effective genetic treatments as well as ongoing clinical trials. In addition, difficulties and moral issues are discussed, covering issues like delivery strategies, side effects, and moral questions about the use of gene editing in the treatment of various illnesses. Lastly, future outlooks and conjectures regarding possible developments, avenues for further study, and the prospects for genetic therapies in the treatment of uncommon neurodegenerative illnesses are discussed.

1. Introduction

Rare neurodegenerative diseases represent a critical area of study in biomedical research due to their profound impact on individuals’ lives and the broader healthcare landscape. Despite their rarity, these conditions collectively affect a significant number of people worldwide, often leading to debilitating symptoms and premature death.

Understanding the underlying causes of these illnesses offers prospective options for therapeutic action in addition to fundamental understanding of neurobiology. Furthermore, research on rare neurodegenerative illnesses can reveal common pathways with more prevalent neurological disorders, which can guide the development of treatments across a spectrum of conditions. Furthermore, new genetic abnormalities linked to various illnesses have been found thanks to developments in genomic technologies, which have made it easier to classify diseases accurately, diagnose patients early, and develop individualized treatment plans.

Figure 1 shows a simplified flowchart to outline a generic overview and the general process for diagnosing and managing rare neurodegenerative disorders.

Figure 1.

The process begins with the identification of presenting symptoms suggestive of a neurological disorder. These may include motor or cognitive impairment, sensory changes, or autonomic dysfunction. A comprehensive neurological examination is conducted to assess motor function, sensation, reflexes, coordination, and cognitive status. Imaging studies such as MRI or CT scans may be performed to visualize structural abnormalities in the brain or spinal cord. Blood tests, cerebrospinal fluid analysis, or other laboratory investigations may be conducted to assess metabolic, infectious, or autoimmune factors that could contribute to neurological symptoms. In cases where a genetic cause is suspected, genetic testing may be performed to identify specific mutations associated with neurodegenerative disorders. Additional tests or procedures may be necessary to confirm the diagnosis, such as muscle biopsy, nerve conduction studies, or specialized imaging techniques. A multidisciplinary team, including neurologists, geneticists, neuropsychologists, and other specialists, may be involved in the evaluation and management of rare neurodegenerative disorders. Patients may receive supportive care to address symptoms and improve quality of life, including physical therapy, occupational therapy, speech therapy, and psychological support. If available, disease-specific treatments or therapies targeting the underlying cause of the disorder may be initiated. Patients may be eligible to participate in clinical trials investigating novel therapies or interventions for rare neurodegenerative disorders. The process concludes with ongoing monitoring, management of symptoms, and support for patients and their families.

Classification of these disorders can be based on a number of criteria, including disease onset and progression. Early-onset diseases are those that manifest symptoms at a young age, frequently before adulthood. Tay-Sachs disease, Niemann-Pick disease, and juvenile Huntington’s disease [1] are a few examples. The genetic foundation, pathophysiology, and clinical manifestations of Tay-Sachs disease, Niemann-Pick disease, and juvenile Huntington’s disease are summarized in Figure 2. The figure also provides the genes linked to each disease, the consequences of mutations on enzyme or protein function, and the symptoms that result from each disorder. Each gene is depicted with its normal function, mutation, and the effect of the mutation on nervous system performance.

Figure 2.

Three genetic disorders: Tay-Sachs disease, Niemann-Pick disease, and Juvenile Huntington’s disease, along with the associated mutations and their effects on neurological function. HEXA gene (Tay-Sachs disease): results from mutations in the HEXA gene, leading to deficient or non-functional Hex-A enzyme. Accumulation of GM2 gangliosides in neurons causes progressive neurological dysfunction. Individuals with Tay-Sachs disease experience developmental regression, muscle weakness, seizures, and early death. SMPD1 gene (Niemann-Pick disease): caused by mutations in the SMPD1 gene, resulting in deficient or non-functional acid sphingomyelinase (ASM) enzyme. Accumulation of sphingomyelin in cells leads to progressive neurological dysfunction. Niemann-Pick disease is characterized by hepatosplenomegaly, progressive neurological decline, and early death. HTT gene (Juvenile Huntington’s disease): disease arises from mutations in the HTT gene, causing an abnormal expansion of CAG repeats and production of mutant huntingtin protein. Accumulation of mutant huntingtin protein in neurons leads to progressive neurological dysfunction. The disease manifests with movement disorders, cognitive decline, and behavioral changes, typically starting in childhood or adolescence.

Contrary to disorders that typically occur later in life, such as some forms of atypical Parkinsonism or certain types of hereditary ataxias, which are classified as late-onset. An alternative way of approaching these disorders is through their clinical manifestations. Conditions affecting motor functions, including Parkinson’s disease, Huntington’s disease, and certain forms of ataxia, are termed movement disorders; these are diseases primarily characterized by cognitive decline and dementia, like frontotemporal dementia, certain forms of familial Alzheimer’s disease, and prion diseases are presenting cognitive impairment. And finally, there are those who manifest mixed phenotypic profiles, such as amyotrophic lateral sclerosis (ALS), which present with a combination of motor impairment and cognitive decline.

The genetic basis of the disease varies, and the number of genes involved. Polygenic or multifactorial disorders, like sporadic forms of Alzheimer’s disease, which are influenced by multiple genetic and environmental factors, are more complex to understand than monogenic conditions (conditions caused by a single genetic mutation), such as Huntington’s disease or familial forms of ALS. Nevertheless, there are differences in the involvement of cellular components. For instance, disorders like Tay-Sachs disease and Niemann-Pick disease, which arise from the build-up of substances within lysosomes, differ from protein aggregation disorders, which are marked by the aggregation of proteins in the brain, such as prion diseases, Parkinson’s disease, and Alzheimer’s disease.

Other examples of diseases featuring abnormal aggregation of the protein tau, including conditions like frontotemporal dementia and certain forms of atypical parkinsonism (tauopathies), are classified differently from synucleinopathies, which are marked by the accumulation of alpha-synuclein, like Parkinson’s disease and multiple system atrophy.

This classification is wide and subject to change when new genetic and molecular pathways underlying various illnesses are discovered through continued research. A range of distinct diseases with their own clinical manifestations, underlying genetic causes, and modes of disease progression may fall under each classification.

2. Genetic mutations and rare neurological diseases: understanding the underlying conditions

Understanding the genetic alterations associated with rare neurological disorders is essential for creating targeted treatments and precision medicine methodologies. New gene variants and molecular pathways are being found by means of advanced genetic sequencing technology, which opens up new avenues for the development of therapeutic medicines targeted at reducing or repairing the underlying genetic defects responsible for these debilitating neurological illnesses.

All are characterized by the progressive degeneration of the nervous system due to mutations and variations in specific genes which play a pivotal role in the system’s pathogenesis. These underpinnings are crucial for accurate diagnosis, prognosis, and the development of targeted treatments.

Trinucleotide repeat expansions are a prominent class of uncommon neurological illnesses in which the amplification of particular DNA sequences results in aberrant protein synthesis and cellular malfunction. A classic example is Huntington’s disease (HD), which is defined by an expanded CAG repeat in the chromosome 4 HTT gene. The age at which symptoms appear and the severity of the disease are correlated with the length of this repeat sequence. Similar to this, a CGG repeat expansion in the FMR1 gene causes fragile X syndrome, which manifests as a variety of neurological and behavioral problems along with intellectual incapacity.

Spinal Muscular Atrophy (SMA) is primarily caused by mutations in the Survival Motor Neuron 1 (SMN1) gene, which is located on chromosome 5q13.2 [2]. The SMN1 gene encodes the survival motor neuron (SMN) protein, which is essential for the maintenance and function of motor neurons in the spinal cord. Without adequate levels of SMN protein, motor neurons degenerate, leading to muscle weakness and atrophy characteristic of SMA. The most common mutation associated with SMA is a deletion of exon 7 in the SMN1 gene. Exon 7 deletion results in a truncated or non-functional SMN protein. Individuals with SMA typically have two copies of the SMN1 gene, one inherited from each parent. However, in SMA patients, both copies of the SMN1 gene are usually affected by mutations, leading to a deficiency in functional SMN protein.

In addition to SMN1 gene mutations, there is a closely related gene called SMN2, which is nearly identical to SMN1 but differs in a critical region that affects alternative splicing. The SMN2 gene produces a smaller amount of full-length SMN protein compared to SMN1 due to alternative splicing events that often exclude exon 7. However, some portion of SMN2 transcripts retain exon 7, resulting in the production of functional SMN protein. The severity of SMA is influenced by the number of copies of the SMN2 gene and the level of functional SMN protein produced. Generally, individuals with more copies of the SMN2 gene tend to have milder forms of SMA due to higher levels of functional SMN protein. However, other genetic and environmental factors can also modulate disease severity.

Another group comprises lysosomal storage disorders, such as Tay-Sachs Disease and Niemann-Pick Disease, resulting from mutations in genes involved in lysosomal function [3, 4, 5]. Tay-Sachs Disease is caused by mutations in the HEXA gene, leading to the accumulation of GM2 gangliosides in nerve cells and subsequent neurodegeneration [6]. Niemann-Pick Disease involves mutations in NPC1 or NPC2 genes, causing impaired lipid metabolism and the buildup of lipids in cells, particularly in the brain [7].

Neurodegenerative conditions like Alzheimer’s Disease (AD) and Parkinson’s Disease (PD) are associated with protein misfolding and aggregation. AD involves mutations in genes like APP, PSEN1, and PSEN2, resulting in the aberrant processing of amyloid precursor protein and the accumulation of beta-amyloid plaques in the brain. PD, while often sporadic, can be linked to mutations in genes like SNCA (alpha-synuclein), LRRK2, and Parkin, leading to the formation of Lewy bodies and dopaminergic neuron degeneration.

Polyglutamine disorders, exemplified by various Spinocerebellar Ataxias (SCAs), are characterized by CAG repeat expansions in different genes (e.g., ATXN1, ATXN2, ATXN3), resulting in ataxia, movement impairment, and other neurological symptoms. These disorders exhibit genetic anticipation, wherein successive generations tend to have earlier disease onset and increased severity due to repeat expansion.

Amyotrophic Lateral Sclerosis (ALS) is a motor neuron disease with both sporadic and familial forms. Familial ALS can result from mutations in genes like C9orf72, SOD1, FUS, and TARDBP, impacting motor neuron function and survival. These mutations disrupt cellular processes, including RNA metabolism, protein quality control, and cytoskeletal dynamics, leading to motor neuron degeneration and subsequent muscle weakness and paralysis.

Prion diseases, such as Creutzfeldt-Jakob Disease (CJD), involve the misfolding of the prion protein (PRNP gene), leading to the accumulation of abnormal prion proteins in the brain. This results in rapid neurological deterioration, cognitive decline, and movement abnormalities.

3. Emerging therapeutic approaches

Emerging and novel therapy modalities for rare neurological illnesses are varied and always changing. They show the increasing sophistication and diversity of solutions being created to deal with difficult situations. Research in these areas needs to continue receiving substantial funding in order to improve patient outcomes and quality of life.

Gene therapy involves delivering functional copies of a gene to compensate for mutations causing the disorder. In rare neurological disorders, this approach aims to correct genetic defects responsible for the condition. Techniques such as viral vectors, including adeno-associated viruses (AAV), are often used to deliver therapeutic genes to target cells. Recent advancements in gene editing technologies like CRISPR-Cas9 hold promise for precise gene correction.

Onasemnogene abeparvovec (Zolgensma) is an innovative gene therapy approved by the FDA for the treatment of pediatric patients less than 2 years of age diagnosed with SMA [8, 9, 10, 11, 12, 13, 14, 15]. It works by delivering a functional copy of the SMN1 gene to replace the defective gene responsible for SMA, addressing the root cause of the disease. This therapy is administered via a one-time intravenous infusion. Clinical trials and real-world experiences have shown promising results with Zolgensma. Many infants treated with this gene therapy have demonstrated significant improvements in motor function, increased muscle strength, and milestone achievements that would not have been possible without treatment. Some children who received Zolgensma have achieved the ability to sit, stand, or even walk independently, depending on the severity and type of SMA.

However, a number of variables, such as the age at which treatment is started, the severity of the illness, and other individual characteristics, may affect how each person reacts to Zolgensma. It is important to remember that, despite Zolgensma’s impressive efficacy, it might not always fully reverse the symptoms of SMA or restore motor function, particularly in situations where irreversible motor neuron loss has already taken place.

As patients are followed up after treatment, researchers are still examining the long-term effects and durability of Zolgensma to assess the therapy’s long-term safety, efficacy, and influence on the course of the disease. CRISPR-based interventions have shown significant potential in addressing rare neurodegenerative diseases by offering precise genome editing capabilities. While this technology is still in its early stages for clinical use in treating these conditions, research and preclinical studies have demonstrated promising results in targeting genetic mutations associated with these disorders.

In precision editing of mutations, CRISPR/Cas9 technology enables precise modification of the DNA sequence, allowing for targeted correction of disease-causing mutations responsible for various rare neurodegenerative disorders [16]. Researchers are exploring ways to utilize CRISPR to edit out or correct genetic mutations linked to conditions such as Huntington’s disease, certain forms of familial ALS, and other monogenic neurodegenerative diseases. One potential approach involves correcting or modifying the genetic mutations responsible for these diseases in affected cells or tissues. For instance, in Huntington’s disease, researchers aim to reduce or eliminate the production of the mutant huntingtin protein using CRISPR-based strategies. Another approach involves modifying the expression of genes associated with disease progression to potentially slow down or halt neurodegeneration.

However, efficiently getting CRISPR components into the brain and into particular types of neurons is a big hurdle. For CRISPR-based therapeutics to be safe and effective, precise editing without unwanted genomic modifications is essential (prevention of off-target effects). Furthermore, regulation and careful consideration must be given to the ethical concerns of germline editing, potential unexpected consequences, and long-term impacts of genetic modifications.

Clinical trials assessing the use of CRISPR/Cas9 technology in treating certain neurodegenerative diseases, are being planned or are in early stages to assess safety and therapeutic potential [17, 18, 19, 20, 21, 22]. Specifically, Leber congenital amaurosis 10 (LCA10) is a rare genetic disorder causing early-onset blindness. EDIT-101, developed by Editas Medicine, is a CRISPR-based gene editing therapy designed to treat LCA10 by targeting mutations in the CEP290 gene. Editas Medicine has initiated clinical trials for EDIT-101. In Huntington’s disease, CRISPR-based gene editing approaches are being investigated to selectively silence or correct the mutant HTT gene. However, clinical trials specifically using CRISPR-Cas9 for Huntington’s disease are still in the very early stages. In ALS, CRISPR-Cas9 technology has been used in preclinical research to target genes associated with ALS, such as C9orf72 or SOD1, for potential therapeutic intervention. Clinical trials involving CRISPR-Cas9 for ALS are not yet underway, but the technology holds promise for future treatments.

Short, synthetic nucleic acid molecules that target RNA are used in antisense oligonucleotide treatment (ASO), which modifies gene expression [23]. This method is especially helpful for conditions like spinal muscular atrophy (SMA) and different types of muscular dystrophy that are brought on by abnormal RNA processing or splicing. Small compounds can interact with particular targets, such as enzymes or receptors, to regulate biological processes. Finding new targets or repurposing current medications for different applications are common steps in the development of small-molecule treatments for uncommon neurological illnesses. These treatments can focus on a number of pathways, including neurotransmitter signaling, protein aggregation, and neuroinflammation, that are implicated in the pathophysiology of disease.

Stem cell-based therapies hold promise for rare disorders by replacing damaged or lost cells, promoting tissue repair, or modulating the immune response. These approaches involve transplanting stem cells, either from exogenous sources or through the reprogramming of patient-derived cells, into the affected tissues. Stem cell therapy is being explored for conditions like Parkinson’s disease, Huntington’s disease, and certain types of leukodystrophies. Enzyme Replacement Therapy (ERT) is a treatment approach used for rare neurological disorders caused by enzyme deficiencies, such as lysosomal storage disorders (e.g., Gaucher disease, Pompe disease). It involves administering recombinant enzymes to replace the deficient enzyme and restore normal metabolic function [24]. ERT can improve symptoms and slow disease progression in affected individuals. RNA Interference (RNAi) is a mechanism for silencing specific genes by targeting complementary RNA sequences. RNAi-based therapies utilize small interfering RNAs (siRNAs) or short hairpin RNAs (shRNAs) to degrade target mRNAs, thereby reducing the expression of disease-causing genes. This approach is being investigated for various rare neurological disorders, including amyotrophic lateral sclerosis (ALS) and Huntington’s disease. And lastly, immunotherapy strategies aim to modulate the immune system’s response to treat neuroinflammatory and autoimmune disorders. Approaches include monoclonal antibodies targeting specific immune cells or cytokines, as well as immune checkpoint inhibitors to enhance immune responses against pathogens or tumor cells. Immunomodulatory therapies are being explored for conditions like multiple sclerosis, neuromyelitis optica, and certain autoimmune encephalitides.

4. Challenges and considerations

There are several hurdles such as delivery methods, off-target effects, and ethical considerations related to gene editing in the context of treating rare neurological diseases.

Regarding delivery modalities, a significant challenge is delivering gene editing tools across the BBB to target specific cells within the central nervous system (CNS). Various strategies are being explored, including viral vectors, nanoparticles, exosomes, and cell-penetrating peptides, to facilitate efficient delivery into the CNS. Achieving cell specificity and ensuring that gene editing tools reach the desired cell types without affecting non-targeted cells is also extremely critical. Selective targeting methodologies, such as engineered viruses or nanoparticles with cell-specific ligands, are under investigation to enhance precision. Furthermore, developing techniques that allow direct in vivo delivery of gene editing tools to specific regions of the brain or spinal cord while minimizing systemic side effects is proving difficult [25].

Unintended genetic modifications causing off-target effects must be avoided, in turn to avoid unintended non-specific alterations in the genome. Enhancing the precision and accuracy of gene editing technologies, such as CRISPR/Cas systems, to minimize off-target effects must be of primary focus. A comprehensive assessment of potential long-term consequences, including genomic stability, unintended mutations, and potential tumorigenesis, is essential before the widespread clinical application of these technologies. Scientists are investigating involving modified Cas enzymes and guide RNAs to enhance the specificity of gene editing tools, reducing off-target effects while maintaining on-target efficiency.

Ethically, germline editing raises concerns regarding the permanent alteration of the genome and potential heritability of edited genes, impacting future generations. Stringent ethical guidelines and regulatory frameworks are essential to address the ethical implications of germline editing in the context of rare (and other) diseases. Ensuring informed consent and respecting patient autonomy, particularly in vulnerable populations or pediatric cases, is crucial when considering experimental gene editing therapies. But it does not stop there: ethical considerations extend to ensuring equitable access to gene editing therapies disparities in availability, affordability, and distribution of these treatments across different populations.

Addressing these hurdles requires collaborative efforts among researchers, clinicians, regulatory bodies, and ethicists for developing innovative, safe, and effective gene editing approaches diseases. Rigorous preclinical studies continued advancements in delivery technologies, thorough assessment of safety profiles, and transparent ethical frameworks are essential in navigating these challenges and ensuring responsible development and implementation of gene editing therapies for neurodegenerative disorders.

5. Conclusion

Rare neurodegenerative diseases encompass a heterogeneous group of disorders characterized by progressive degeneration of the nervous system, resulting in debilitating neurological symptoms. Despite their rarity individually, and collectively, these disorders pose significant challenges to patients, families, and healthcare systems worldwide. Over the past few decades, substantial progress has been made in understanding the underlying pathophysiology, genetic mechanisms, and potential therapeutic strategies for these conditions. In this conclusive scientific section, we will explore recent advancements, challenges, and future directions in the field of rare neurodegenerative diseases.

Recent advancements in rare neurodegenerative diseases have been propelled by breakthroughs in genetics, molecular biology, and neuroscience. The advent of next-generation sequencing technologies has revolutionized the identification of disease-causing genetic variants, enabling the discovery of novel genes associated with rare neurodegenerative disorders. Furthermore, advancements in animal models and induced pluripotent stem cell (iPSC) technology have facilitated the elucidation of disease mechanisms and the development of preclinical models for drug discovery and testing. One of the most significant advancements in recent years has been the emergence of gene therapy as a promising treatment approach for rare neurodegenerative diseases. Gene therapy holds great potential for correcting underlying genetic defects, slowing disease progression, or even providing a cure for some disorders. Clinical trials utilizing gene therapy vectors, such as adeno-associated viruses (AAVs) [26, 27, 28, 29], have shown promising results in diseases like spinal muscular atrophy (SMA), Batten disease, and familial amyloid polyneuropathy (FAP), among others. In addition to gene therapy, other therapeutic modalities, such as small molecule drugs, antisense oligonucleotides (ASOs), and monoclonal antibodies, are also being investigated for their potential to target specific pathways implicated in rare neurodegenerative diseases. These advancements highlight the growing momentum in the field and the increasing hope for effective treatments for patients with these devastating disorders.

Despite significant progress, rare neurodegenerative diseases continue to present formidable challenges to researchers, clinicians, and patients alike. One of the most pressing challenges is the heterogeneity of these disorders, both in terms of clinical presentation and underlying genetic etiology. The rarity of individual diseases poses difficulties in conducting large-scale clinical trials and accruing sufficient patient cohorts for meaningful research studies. Another major challenge is the lack of disease-modifying treatments for many rare neurodegenerative diseases. While symptomatic therapies may help alleviate some symptoms and improve quality of life, they do not address the underlying cause of the disease or halt its progression. Developing effective disease-modifying therapies requires a deeper understanding of the molecular pathways involved in neurodegeneration and the identification of druggable targets. Furthermore, the translation of promising preclinical findings into clinically viable treatments faces numerous hurdles, including regulatory approvals, manufacturing challenges, and cost considerations. The high cost of developing and delivering novel therapies poses significant barriers to access for patients, particularly those in resource-limited settings or without adequate healthcare coverage.

Looking ahead, several promising avenues hold potential for addressing the challenges posed by rare neurodegenerative diseases and advancing the field toward effective treatments and cures. Collaborative efforts among researchers, clinicians, patient advocacy groups, and industry partners are essential for accelerating the pace of discovery and translation. Precision medicine approaches, leveraging advances in genomics, proteomics, and imaging technologies, offer the promise of personalized therapies tailored to individual patients’ genetic and molecular profiles. Biomarker discovery and validation are critical for identifying disease progression markers, monitoring treatment response, and stratifying patients for clinical trials. Moreover, the continued development of innovative therapeutic modalities, such as RNA-based therapies, gene editing technologies (e.g., CRISPR-Cas9), and gene silencing approaches, holds tremendous potential for addressing the underlying genetic defects in rare neurodegenerative diseases [30]. Strategies for optimizing drug delivery to the central nervous system (CNS) and overcoming the blood-brain barrier are also being actively pursued to enhance therapeutic efficacy. In addition to therapeutic interventions, efforts to improve patient care and support services are essential for addressing the holistic needs of individuals and families affected by rare neurodegenerative diseases. Multidisciplinary care teams, including neurologists, genetic counselors, physical and occupational therapists, and social workers, play a crucial role in providing comprehensive care and support across the continuum of the disease.

In conclusion, rare neurodegenerative diseases represent a complex and challenging group of disorders with significant unmet medical needs. While recent advancements have provided hope for effective treatments, numerous challenges persist, including disease heterogeneity, lack of disease-modifying therapies, and barriers to translation. However, with continued investment in research, collaboration, and innovation, there is optimism for the future of rare neurodegenerative disease research and the development of transformative therapies that will improve the lives of patients and families affected by these devastating conditions.

Conflict of interest

The author was Head of Medical Affairs of Novartis Pharmaceuticals Islands. The company is the manufacturer of Zolgensma used in the treatment of SMA.