The realm of gene therapy is ever-changing, with new possibilities and challenges continually emerging. With over 6,000 genetic disorders and the list growing, gene therapy stands as a potential panacea for monogenic diseases by altering an individual’s genetic makeup. Notable milestones, such as alipogene tiparvovec’s approval in 2012 and voretigene neparvovec’s endorsement in 2017, signified the transformative power of gene therapy. However, since these landmarks, the field has witnessed numerous developments and confronted its share of obstacles.

Gene Therapy: A Ray of Hope for Neuromuscular and Neurodegenerative Diseases

Neuromuscular diseases (NMDs) and neurodegenerative diseases (NDDs) are often progressive, life-shortening illnesses, many of which lack viable treatments. For this reason, NMDs and NDDs with genetic origins have become promising targets for gene therapy, aiming to address the root cause—the defective genes.

A significant turning point occurred in 2019 when the US Food and Drug Administration approved onasemnogene abeparvovec, an AAV therapy designed to combat spinal muscle atrophy (SMA). This marked a pivotal moment in NMD treatment. SMA, linked to mutations in the SMN1 gene, results in the gradual loss of motor neurons, leading to progressive muscle weakness and, in severe cases, respiratory failure. Onasemnogene abeparvovec involves delivering a functional copy of SMN1 via an AAV9 vector, administered through intravenous injection. Clinical trials showed improved functional and survival outcomes compared to the natural progression of the disease.

Experts like Kathrin Meyer, an assistant professor at the Ohio State University, are exploring the potential of gene therapy for various NMDs and NDDs. Their focus extends to Batten disease and neuronal ceroid lipofuscinoses, diseases caused by mutations in lysosome storage genes known as ceroid-lipofuscinosis neuronal (CLN). Their research has demonstrated that AAVs carrying a functional CLN copy can improve lifespan and alleviate brain and behavioral pathology in Batten disease models.

Similarly, Guangping Gao, a professor at the Horae Gene Therapy Center at the University of Massachusetts Medical School, is actively investigating gene therapy as a potential avenue for NMDs and NDDs. Their work includes studying Canavan disease, a fatal recessive NDD caused by mutations in the aspartoacylase (ASPA) gene. AAV-mediated delivery of a functional ASPA copy showed drastic improvements in neuropathology, myelination, and motor function. This research has not only paved the way for therapeutic interventions but also deepened our understanding of disease pathophysiology.

Gene therapy offers various strategies, from replacing defective genes with functional copies to using AAVs for delivering short hairpin (shRNA) or interfering RNAs (RNAi) to silence toxic genes. It has shown promise in slowing the progression of diseases like amyotrophic lateral sclerosis (ALS).

Moreover, gene therapy can support damaged tissues by delivering genes that strengthen muscles or promote nerve regeneration. It’s even poised to correct genes using base-editing CRISPR-Cas technology, addressing both loss-of-function and gain-of-function mutations.

Overcoming Challenges in Gene Therapy: The Immune Response

Despite its potential, gene therapy faces challenges, and one of the most prominent is the immune response. AAVs and their transgene cargo can trigger innate or adaptive immune reactions, affecting transduction efficiency and long-term gene expression, and increasing the risk of adverse events. Methods to mitigate these responses include altering the injection method for AAV administration, removing preexisting AAV antibodies, and engineering the AAV capsid, vector genome, and transgene to lower their immunogenicity. Some scientists are even employing microRNA-based strategies to evade immune cells.

Tailored Tissue Targeting and Transduction

Enhancing tissue specificity and transduction efficiency is another major goal in gene therapy research. Researchers are exploring various AAV serotypes with distinct capsid variations, each with different tissue specificity and the ability to cross the blood-brain barrier. They aim to achieve widespread transgene delivery, even to deep layers of tissue.

Engineered or evolved AAV capsids hold the potential to improve targeting and transduction, reducing the required dosage and associated risks. Further innovations include tissue-specific, optimized transgenes to enhance expression within the target tissue while dampening innate immune responses.

Balancing Gene Expression and Modulation

Stable, durable gene expression at physiological levels is a key goal in gene therapy research. Ensuring controlled expression is vital, as uncontrolled overexpression can lead to toxic effects. Additionally, the ability to turn off gene therapies, particularly those involving CRISPR-Cas cargo, is crucial. Understanding the target gene’s native environment and disease mechanisms is a complex but essential aspect of gene therapy research.

Overcoming Price and Accessibility Barriers

While gene therapies have transformed outcomes for some patients, their high costs limit accessibility. Early diagnosis is another challenge for NMDs and NDDs caused by rare mutations. To advance gene therapy, streamlining manufacturing, standardizing regulatory aspects, and making sequencing technologies more accessible are essential steps.

In conclusion, gene therapy offers a promising avenue for treating genetic diseases at their core. While significant strides have been made, challenges persist. Researchers are diligently working to overcome these obstacles to make gene therapy accessible and effective for a broader range of patients.

By Impact Lab