Exclusive Interview with Dr. Ramón Cacabelos on the Future of Genomic Medicine in Neurological Disorders

On February 13, we had the privilege of interviewing Dr. Ramón Cacabelos, a prominent figure in genomic medicine. Dr. Cacabelos shared his expert views on the evolving landscape of genomic medicine, particularly in the treatment of neurological disorders such as Alzheimer's, Parkinson's, and multiple sclerosis.

Below are the key takeaways from the interview:

What are the key differences between traditional therapeutic approaches and genomic-based treatments for CNS diseases?

Traditional therapeutic approaches for central nervous system (CNS) diseases generally focus on alleviating symptoms and modulating neurotransmitter systems, while genomic-based treatments aim to address the underlying molecular and genetic causes of these disorders. For example, mechanisms of action of traditional approaches rely on symptomatic relief with small-molecule drugs or biologics that modulate neurotransmitter activity (e.g., dopamine, serotonin) or reduce inflammation, thereby alleviating symptoms such as pain, cognitive impairment, or motor dysfunction. These therapies are generally not tailored to the patient’s specific genetic makeup but rather target pathways known to be dysregulated in a large group of patients. In contrast, genomic-based treatments in precision medicine use genetic and molecular information to target specific mutations, gene expression profiles, or pathogenic pathways. This includes personalized pharmacogenetics, gene therapy, antisense oligonucleotides, and CRISPR-based gene editing. Another important issue is disease modification, which is aimed at correcting or compensating for the underlying genetic defects that contribute to disease progression rather than providing symptomatic relief alone. Concerning personalization, traditional approaches use generalized treatments that usually follow a “one-size-fits-all” strategy where the same medication is prescribed to large populations with the same clinical diagnosis. Doses and drug choices are often based on population averages, which may not account for individual variability. In contrast, genomic-based treatments use tailored therapies with customized treatments based on an individual’s genomic profile, potentially leading to better efficacy and fewer adverse effects.

What recent advancements in genomic medicine have shown promise in treating neurological disorders like Alzheimer's, Parkinson's, or multiple sclerosis?

Recent advancements in genomic medicine have opened promising avenues for treating neurological disorders by targeting the underlying genetic and molecular mechanisms. Gene therapy and RNA-based approaches in Alzheimer's disease are exploring ways to modulate the expression of genes involved in amyloid processing and tau pathology. For instance, researchers are testing viral vector-mediated delivery of therapeutic genes that aim to enhance the clearance of amyloid-beta or reduce tau hyperphosphorylation. In Parkinson's disease, gene therapy has been used to deliver genes encoding enzymes involved in dopamine synthesis (e.g., AADC, tyrosine hydroxylase) directly to the brain, with several clinical trials showing improvements in motor symptoms. Additionally, RNA-based therapies, such as antisense oligonucleotides, are being explored to target genetic mutations like LRRK2 or SNCA. In multiple sclerosis, genomic approaches are focusing on modulating the immune response by targeting specific genes involved in autoimmunity. Although MS is primarily an autoimmune disorder, genomic medicine aims to identify and modulate genetic factors that predispose individuals to aberrant immune responses against myelin. Genome editing technologies, particularly CRISPR/Cas9, are being investigated to correct pathogenic mutations directly in affected cells. In Parkinson's disease, preclinical studies are exploring CRISPR-based strategies to correct mutations in genes like LRRK2. While these approaches are still in the early stages, they offer the potential for durable, one-time treatments by permanently altering disease-causing genetic variants. Advances in genomic sequencing and bioinformatics have led to the identification of genetic biomarkers that can predict an individual’s risk of developing these disorders and their likely response to specific treatments. For instance, stratifying patients based on their APOE genotype in Alzheimer's disease helps tailor treatment strategies, while genome-wide association studies (GWAS) in Parkinson’s and MS are revealing new molecular targets. Personalized genomic profiles are increasingly used to guide clinical decision making, ensuring that patients receive therapies best suited to their genetic makeup. Epigenetic modifications, which regulate gene expression without altering the DNA sequence, are also being targeted. Drugs that modulate DNA methylation or histone acetylation are under investigation for their potential to reverse pathological gene expression patterns seen in Alzheimer's and other neurodegenerative disorders.

What are the main challenges in applying genomic medicine to CNS diseases, particularly in terms of delivery systems and gene therapy?

Recent advances in genomic medicine offer great promise for treating CNS disorders; however, several challenges remain, especially regarding the delivery of gene therapies to the brain and ensuring long-term safety and efficacy. Concerning delivery systems and blood-brain barrier (BBB) penetration, limited permeability is a major challenge. The BBB is a highly selective barrier that prevents most large molecules, including many viral vectors and nucleic acids, from entering the brain. Effective delivery systems -such as engineered viral vectors (e.g., adeno-associated viruses, lentiviruses), nanoparticles, or exosome-based carriers- must be designed to cross the BBB safely while avoiding an immune response. Once across the BBB, delivery systems must accurately target affected cells without affecting healthy tissue. Another important issue is safety and immune response. Viral vectors and gene editing components (like CRISPR/Cas9) may trigger an immune response that can reduce therapeutic efficacy or cause adverse effects. Gene editing poses risks of unintended modifications to the genome, which could lead to unforeseen complications or toxicity in the CNS. With regard to long-term expression, ensuring stable, controlled gene expression over time without long-term side effects remains a challenge. It is also important to keep in mind the complexity and heterogeneity of CNS disorders. CNS diseases such as Alzheimer’s, Parkinson’s, and multiple sclerosis have complex and multifactorial etiologies. Tailoring gene therapies to address the underlying genetic and molecular mechanisms specific to each patient (personalized medicine) is still in development. The brain comprises various cell types (neurons, astrocytes, microglia, oligodendrocytes) and therapies need to be precisely targeted to the relevant population to be effective. Some regulatory and ethical challenges also deserve consideration. Extensive preclinical and clinical testing is required to ensure safety, which can be time-consuming and costly. As genomic medicine involves permanent genetic modifications, ethical concerns about long-term consequences, germline alterations, and equitable access to therapies need to be addressed.

Our journal also covers the exploration of genomic medicine. What do you see as the potential of genomic medicine in the context of neurological diseases?

Genomic medicine must focus its attention in the immediate future on three priority areas: pathogenesis, diagnosis, and treatment. At present, only approximately 10% of human pathology is known about the pathogenic mechanisms and primary causes. Therefore, functional and structural genomics, epigenetics, transcriptomics, proteomics, and metabolomics must serve to deepen our understanding of the mechanisms that explain why we get sick. As far as diagnosis is concerned, it must be taken into account that 80% of adult and old-age pathologies are actually destroying our brain decades before symptoms appear. When Alzheimer's or Parkinson's becomes clinically manifest, there are already so many billions of dead neurons that no conventional treatment will be able to restore the lost function. Of course, no treatment will resuscitate dead neurons. Therefore, we need to develop presymptomatic biomarkers to identify the risk of suffering from these neurodegenerative diseases many years before they show symptoms and to interfere with their progression with an effective prophylactic and preventive intervention. Finally, pharmacogenomics and pharmacoepigenetics have to help us personalize the treatment in terms of safety and efficacy. Studies carried out by my group in recent years show that, considering the 60 pharmacogenes with the greatest clinical significance, from a genophenotypic point of view, only 20-30% of the population is a normal metabolizer for 80% of the commonly used drugs, approved by the FDA in the United States or the EMA in Europe. This means that when we administer drugs in bulk, by trial and error, without knowing the pharmacogenetic profile of the patients we treat, in more than half of the cases, we do not induce any therapeutic effect or, what is worse, we induce toxicity and adverse effects. The epidemiological confirmation of this fact is that currently, the misuse of drugs is becoming the third health problem in developed countries, behind cardiovascular accidents and cancer. The consequence of this in public health problem is that approximately 10% of hospital admissions in the USA and the EU are due to the misuse of drugs. Therefore, genomic medicine needs to be implemented with some urgency, intensifying educational programs for health professionals, who - unfortunately - do not reach 5% of the number of doctors and pharmacists who are familiar with genomics and pharmacogenomics.

As an outstanding scientist with a very busy schedule, how do you manage to balance your work and personal life?

When you are committed to your job and when the health of your fellow human beings is your top priority, it is very difficult to maintain a balance between your work and your private life. In the struggle to achieve a little balance, there are always two victims: your family, from whom you steal years of life and participation in the education of your children - if you have them - or in sharing your life with the people you love; and your hours of rest and leisure, which end up reduced to the bare minimum, especially your hours of sleep. Even so, if your family environment is happy and your emotional stability is solid, everything is possible in this life.

About Dr. Ramón Cacabelos:

Editor: Iris Zhang
Language Editor: Catherine Yang
Production Editor: Ting Xu
Respectfully Submitted by the Journal Editorial Office of Journal of Translational Genetics and Genomics