CGT can effectively treat chronic, rare diseases precisely targeting the root causes, ET HealthWorld

Dr Anis H Khimani, Senior Strategy Leader, Pharma Development, Life Sciences, Revvity spoke to ETHealthworld’s Prathiba Raju on how the cell and gene therapy (CGT) segment is evolving in India. How CGT’s novel modalities will steer the Indian healthcare landscape from traditional approaches that mostly treat symptoms to curing the disorders at the root cause.How is the cell and gene therapy (CGT) segment evolving in India, and how is it transforming the treatment in cancer care, sickle cell anemia, beta-thalassemia, muscular dystrophy, diabetes, and cardiovascular disease? How does it impact new drug development and the future of medicine?

Cell and gene therapies (CGT) is rapidly evolving in India. The segment is emerging to address multiple diseases from chronic conditions to a number of rare genetic disorders. India is a large, growing economy, and healthcare has been one of the key focus areas of investment and growth. Although sickle cell anemia and beta-thalassemia have been prevalent in India with a huge health burden coming from both disorders, there is also an increasing demographic for chronic diseases such as cancer, diabetes and cardiovascular. Stem cell-based replacement therapies are showing promise to treat type-1 diabetes. The novel modalities will steer the Indian healthcare landscape from traditional approaches that mostly treat symptoms to curing the disorders at the root cause. However, challenges such as costs, infrastructure, and clear regulatory guidelines would need to be resolved. Encouraging news is that few years ago the Indian government has released guidelines for the development and commercialization of gene therapy products. In addition, CGT clinical trials in India are increasing via several companies, and there are emerging startups and large biopharma companies focusing on this new therapeutic area.

What is the impact of COVID-19 on the CGT segment? What are some of the significant altering foundations the industry is becoming accustomed to?

Development and commercialization success of every therapeutic modality and its workflows are dependent upon multiple factors that constitute the pillars of the foundation. Key factors include supply chain and related availability of raw materials, shipment, skilled workforce, access to technology, automation, regulatory framework, IT and informatics infrastructure, and clinical trial footprint to name several. A few of these factors, which are detailed below, have been impacted by COVID-19 and majorly affected the CGT industry.

Cell and gene therapy companies have experienced delays or stalled operations due to disruption in obtaining raw material and biological supplies, which had a domino effect in material shortages caused by shipment irregularities.

Logistical and transportation issues, as stated above, have led to shortages or delays in the shipment of materials for clinical trials. There has also been a lack of interaction of clinical trial staff with patients, and sample collection challenges.

On the other hand, the COVID pandemic has also stimulated developments and enhancements in process and manufacturing workflows. The aforementioned challenges have led to lessons learnt, resulting in innovations that enable robust manufacturing processes, automation to drive efficiency and improved safety measures, digitization for continuous and remote monitoring, implementation of better supply chains, swift regulatory reviews and audits, and improved patient safety oversight. In addition, current and future roadmaps across CGT therapeutic development and processes now also include enhanced cross-organization collaborations to leverage strengths and information sharing resulting in accelerated, efficient, and safe delivery of treatments.

Why should we focus more on CGT, particularly for cancer care, neurological disorders, and rare diseases? How does it address the challenges in this space? How is CGT helping to make treatments accessible and affordable?

Historically, the treatment of diseases has focused on alleviating the symptoms. However, with advances in CGT, the opportunity now exists to correct the mutation(s) causing the disease for a permanent cure. Understanding the genetic basis of a disease, and subsequently correcting the gene can be more effective and offers a potential therapeutic path across a number of disorders such as cancer, rare diseases (RD), hematological and neurological abnormalities, among others.

The novel therapeutic approaches pose new technical and clinical challenges. From accurately targeting the diseased tissue to ensuring that the corrected gene is expressing proteins at sufficient level to resolve the clinical symptoms, to accomplishing products that are robust, affordable, scalable, and accessible. At the genetic level, a recent introduction of precise base editing offers more complex multiplexed editing with reduced off-target editing and significantly lowers errors. This approach is expected to reduce the time required to create therapies because editing can be performed concurrently instead of needing to be performed sequentially. One example of base editing, the Pin-point™ system, has been demonstrated as able to knock out immunogenic proteins and knock in a targeted CAR within the same editing reaction, creating an effective functional CAR-T cell line with tumor-killing activity in a single editing reaction.

CGTs are expensive but represent promising treatments for numerous diseases at the genetic level, hence targeting the root cause. Although many of the therapies have been developed in high-income countries (HIC), access to these approaches in low-to-middle-income countries (LMIC) is being driven by local government and academic institutions to eventually make them affordable (Cornetta et al., 2022). India is currently investing in becoming an economical manufacturing center for CGT products. In addition to preclinical studies using viral vectors addressing hemophilia, thalassemia, and other diseases, numerous clinical trials are underway in the country. Also, CAR-T cell trials are currently being supported by the Indian Council of Medical Research (ICMR) (Cornetta et al., 2022). Guidelines for gene therapy products and clinical trials have been developed by ICMR and the Department of Biotechnology (DBT) for gene therapy in India.

What is the potential of viral-vector gene therapy and how it could help in transformative solutions for diseases such as Parkinson’s?

Recombinant viral vectors used in gene therapy have primarily focused on lentiviral, adenoviral, or adeno-associated virus (AAV) genome backbones. AAVs have been the most studied, characterized, and currently successful for use in gene therapy applications. Various AAV serotypes have been widely adopted as vectors for preclinical and clinical delivery. Since AAV is a non-pathogenic parvovirus, recombinant adeno-associated viral (rAAV) vectors have been successful in numerous gene therapy programs; examples include prescription gene therapies for patients with inherited retinal disease (IRD) Leber congenital amaurosis (LCA), to treat spinal muscular atrophy (SMA) in children younger than two years old (Keeler, A.M. 2019), for Hemophilia B (2022), and for pediatric (ages 4 – 5) Duchenne muscular dystrophy (DMD) (2023), which was recently approved by the US Food and Drug Administration (FDA).

Preclinical studies are also underway to treat Parkinson’s Disease (PD). One such study utilizes an AAV vector harbouring the GBA1 gene transported into PD patients that encodes the beta-glucocerebrosidase enzyme. This gene is mutated in Parkinson’s Disease patients causing them to accumulate glycolipids, leading to inflammation and neurodegeneration of brain cells. The introduction of the GBA1 gene enabled improvement in motor function. Further research is ongoing on evaluating the enzyme expression as well as other neurotrophic factors as supplemental mediators to treat or alleviate PD symptoms.

How are new technology platforms being used for generating data that are consistent, reliable, and well-linked? How crucial it is to manage and integrate data generated at all stages of cell and gene therapy right from R&D to real-world use after regulatory approval?

Various technologies and best practices continue to be developed to meet the challenges within the area of CGT. These technologies and tools are used to facilitate workflow management, automation, data analysis, and management, purification, and safety testing to meet regulatory requirements. For example, the full and empty capsid viral characterization of the AAV vector at each step of the workflow enables the assessment of Critical Quality Attributes (CQA) to ensure the identity, purity, potency, and stability of the vector product. Although, current gold standard techniques such as analytical ultracentrifugation (AUC) or transmission electron microscopy (TEM) offer AAV characterization, these are limited by the availability of sample quantities and are laborious. Recent studies have shown that microfluidic, capillary electrophoresis (CE) platforms such as the LabChip® GXII Touch™ facilitate AAV capsid protein (VP1, VP2, VP3) analysis, and full and empty AAV capsid quantification with minimal sample amounts and better throughput (Coll De Peña et al., 2022). It is important to optimize manufacturing processes to reduce the quantity of empty capsids so that patients receive an accurate therapeutic dose of gene therapy. Furthermore, advancements in analytics have significantly increased the amount of data generated throughout CGT workflows, which presents storage and retrieval challenges. Management of the increased data output can be best achieved via automated analytical workflows that enable the organization of data and streamline subsequent analyses. Recent advancements in artificial intelligence (AI) and machine learning facilitate predictability and process design.

What are the key segments that you are working on, and what are your future plans?

Revvity has had decades of track record in enabling scientific endeavor, from basic research through the discovery and development of small and large molecule drugs. We have core capabilities in molecular detection and imaging with solutions to evaluate the corrective genetic information and the molecular tools needed to make the correction, called the payload, as well as the vehicles that deliver the payload into cells, such as vectors derived from harmless viruses. We provide tools and services for gene editing, through viral delivery characterization, and manufacturing and quality control indicators, including automated cell counting and therapy efficacy and safety evaluation. These are all key pillars that researchers and scientists working in CGT can benefit from.

How do you foresee the market for CGTs developing, particularly in the next couple of years? What are the key challenges that are present at the moment when it comes to the genetic testing industry? What steps have to be taken to improve these challenges?

CGT will continue to evolve, overcoming the challenges and limitations, as technological and process innovations continue to enable researchers, developers, and clinicians to make ongoing improvements. Key challenges include the evolving need for optimal genetic payload delivery systems, which can be targeted to specific organ or tissue types with greater efficacy and better safety profiles. Adeno-associated virus (AAV) and lentiviral vectors are most popular for gene and cell therapy deliveries, respectively, but they still need to be optimized for targeted delivery, lower dosage and greater efficacy, minimal immune response, and better safety. Scale-up and manufacturing both have limitations since the vectors and the payload are complex biologics. Compliance oversight to meet stringent and evolving regulatory requirements due to the complexity of the system is another challenge. In addition, a technically skilled workforce is critical to the success of the workflows.

Adoption of automation and digitization, similar to Bioprocessing 4.0 for large molecule drugs, will potentially enable higher manufacturing yields, shorter development cycle times, and implementation of Quality-by-Design (QbD) and Process Analytical Technologies (PAT) for real-time monitoring and feedback control.

The recent global COVID-19 pandemic has set an unprecedented example for cross-disciplinary and cross-functional collaborations that accelerated both vaccine and diagnostic and therapeutic endeavors against the virus. On the heels of such a collaborative model, the adoption of similar academic, industry, regulatory, and clinical stakeholder collaboration will significantly benefit the cell and gene therapy space, all the way from discovery through preclinical and clinical workflows. The formation and management of institutional and industry consortia globally will leverage cross-organizational expertise to further accelerate advancements in CGT.