Why Gene Therapy Companies like Libella Gene Therapeutics are Looking at Colombia for their Clinical Trials?

Libella Gene Therapeutics —a US-based company— recently chose Colombia to conduct a phase I clinical trial that could represent a breakthrough in the treatment of Alzheimer's disease (AD) using gene therapy. The approval of a gene therapy trial in Colombia takes 30-45 days from the date of submission to an ethics committee. This time may be shorter or longer depending on how fast the ethics committee at the health institution (aka research center) evaluates the study documents. This positions Colombia as one of the countries with the fastest approval time (and lowest cost) in Latin America for gene therapy research. 

Gene therapy offers the ability to permanently correct a disease at its most basic level, the genome, and could offer cures for many conditions that are considered incurable. Unlike traditional drugs, which tend to be taken for months or years at a time, gene therapy interventions are intended to be one-off treatments that tackle a disease at its source, repairing faulty DNA and allowing the body to fix itself.

Colombia's clinical research regulation is friendly to gene therapy trials. Resolución 8430 de 1993 from the Colombian Ministry of Health regulates human research with advanced therapies (including gene therapy). Chapter 1 of the resolution states the following conditions for approval of a gene therapy clinical trial in Colombia,

• The legal representative at the clinic must approve it
• The ethics committee at the clinic must approve it
• Patients must sign an informed consent

The approval of a gene therapy trial in Colombia takes 30-45 days from the date of submission to an ethics committee. This time may be shorter or longer depending on how fast the ethics committee at the health institution (aka research center) evaluates the study documents. This positions Colombia as one of the countries with the fastest approval time in Latin America for gene therapy research. 

The human telomerase reverse transcriptase (hTERT) is an enzyme that expression plays a role in cellular aging. It is normally repressed in cells, resulting in progressive shortening of telomeres. Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. 

Aged organisms accumulate telomere-derived DNA damage and it has been demonstrated that it is possible to repair or delay the accumulation of this type of damage through telomerase gene therapy. The present application thus provides the feasibility of using an Adeno-Associated Virus (AAV) delivery system carrying the hTERT gene to extend the telomeres in neurodegenerative disease to prevent the development, delay or reverse the pathology. 

This will have a direct consequence on cognitive function and quality of life in patients with neurodegenerative disease. Adeno-Associated Virus (AAV) vectors are not pathogenic to humans and cause limited and infrequent immune responses. There have been several safety studies performed for these vectors, confirming the benefit of using them for gene delivery and their safety.

During the last few decades, breakthroughs in medicine have resulted in a decline of deaths associated with many major diseases. In contrast, deaths due to neurodegenerative diseases such as Alzheimer’s disease (AD) have steadily increased, in part due to a growing elderly population.

The worldwide prevalence of dementia-related diseases, of which Alzheimer’s is the most common, was estimated to be 36 million people in 2010, and this number is expected to almost double every 20 years. Currently, there is a great need for disease-modifying treatments, as the current standards of care do not delay disease progression. 

With the evidence that autopsies of demented individuals over the age of 65 demonstrate a predominance of lesions normally associated with AD, i.e., neurofibrillary tangles and "senile" (neuritic plaques) (Tomlinson et al., 1968, 1970), the significance of Alzheimer's disease as a public health problem became evident. The correlation of plaque count with the degree of dementia further established the relationship of this pathologic lesion with clinical manifestations (Blessed et al., 1968). 

Early investigators noted its association with dementia and/or plaques (Pantelakis, 1954; Surbeck, 1961), it was more often related to normal aging than to AD until an extensive study of more than 400 AD autopsies revealed its presence in 92% of Alzheimer's disease cases and relative absence in non-Alzheimer's disease patients (Glenner, 1983; Glenner et al., 1981). It has also been associated with intra cortical and leptomeningeal hemorrhage (Torack, 1975), usually in conjunction with AD. 

The underlying mechanisms involved in the pathogenesis of neurodegenerative diseases such as Alzheimer’s are poorly understood. There are currently no curative treatment options but medications and management strategies may temporarily improve symptoms.

A key feature of AD is a decline in cognitive function. Alzheimer's disease is characterized by memory loss, difficulty concentrating and thinking, and changes in personality and behavior (ref). The development of dementia correlates with aging. As one ages structures called telomeres get shorter. A growing body of data shows that telomeres have been involved in the process of neurodegeneration and dementia-related diseases (Flanary et al. 2007, Hamet and Tremblay 2003, Jaskelioff et al. 2011). 

Telomere length has been associated with cognitive decline and could serve as a biomarker for cognitive aging (Devore et al 2011, Insel et al 2012, Klajajevic 2011, Martin-ruiz et al 2006, Yaffe et al 2011). Telomere shortening is a marker of cellular aging and has been associated with dementia risk of AD (Grodstein et al 2008, Jenkins et al 2008). It has been demonstrated that telomere shortening has been associated with cognitive impairment, amyloid pathology and hyperphosphorylation of tau in AD and plays an important role in the pathogenesis of AD via the mechanism of oxidative stress and inflammation. Research suggests that control of the telomere length has the potential to treat many neurodegenerative diseases linked to aging, including Alzheimer's disease.

AAV has become increasingly common as a vector for use in human clinical trials. They have been used in over 183 clinical trials worldwide (Ginn et al, 2017). The increased popularity of AAV vectors reflects the appreciation of the long-term transgene expression observed in animal models and the relative lack of immune response and other toxicities in the models. 

The ability to alter cellular function genetically remains a powerful tool for the treatment of various diseases. Recently, the FDA granted accelerated approval to first gene therapy. This approval under the accelerated approval pathway provides for the approval of drugs that treat serious or life-threatening diseases and was based on adequate and well-controlled studies showing the drug has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients. Safety and efficacy issues still raise concerns, especially when gene therapy is applied to neurological disorders, in which there is limited prior experience. 

It has been shown that AAV-mediated gene transfer can be done safely in the human brain for the treatment of chronic, degenerative neurological diseases (Kaplitt et al, 2007). Showing that AAV-mediated gene transfer can be done safely with no evidence of substantial toxic effects or adverse events for more than 3 years.

Contact us at info@latammarketaccess.com for more information about how you could conduct your gene therapy clinical trial in Colombia.