Seguridad y eficacia terapéutica de la proteína antienvejecimiento klotho para tratar los déficits asociados a la edad y aumentar la longevidad

Joan Roig Soriano

Miguel Chillón Rodríguez

Área de Neurociencias

First, the expression of the different isoforms of KL was increased, using gene therapy vectors, in healthy young animals to study the absence of toxicity of the treatment. The s-KL isoform, unlike others such as p-KL, did not induce adverse effects in any of the different histological and serological studies carried out, suggesting pharmacological safety. Subsequently, the different murine models were treated to analyze the effect of s-KL on the aging process. First, the cognitive abilities during aging of the treated animals improved. This fact was accompanied by an increase in markers of adult neurogenesis in the hippocampus of the brain, and also the normalization of markers involved in inflammatory processes, altered during aging. Second, s-KL also improved the physical abilities of the aged animals, which correlated with a reduction in fibrosis and an increase in muscle regeneration. Third, the treatment induced an improvement in several microstructural parameters associated with osteoporosis. Fourth, animals treated with s-KL had a life expectancy 20% higher than control animals. Finally, after these promising results, aged primate individuals were treated. Nine months after treatment with s-KL, the animals improved their cognitive abilities, suggesting that s-KL could also be effective in humans. The results of this thesis show for the first time the safety and therapeutic efficiency of increasing the s-KL protein to simultaneously treat several age-associated deficits, increasing both quality of life and longevity. Three scientific articles and three patents have been published from this thesis, which we hope will promote the pharmaceutical industrial interest in s-KL and advance towards clinical trials in humans.

After our promising preclinical studies in mice and non-human primates conducted in this thesis, we contacted the Technology Transfer Office (TTO). The TTO received the International Search Report (ISR) and the assessment was made together with ZBM patents, finding a robust strategy to defend the patentability in front of the forthcoming office actions at the territories where the patent will finally be in force. A patent (WO2022/243519 A1) is now published, and current owners (VHIR, UAB, UB, ICREA) have signed a co-ownership agreement that regulates the management aspects and split of revenues if the patent is transferred into the market. We are now looking for partners to further develop an s-KL based therapy, to transition this technology to the pharmaceutical industry. Of note, different international companies as Calico, Rejuveron, and GEBRO pharma have showed interest in the patents generated during this thesis. Indeed, ANEW Medical has already signed confidentiality agreements to preserve our intellectual property (IP) in the use of s-KL for treating ageassociated deficits. Applicability and current actions As our final goal is to achieve to reach the clinical level in humans, and we have no logistical, manufacturing, and financial capacity to reach this, we are currently negotiating with ANEW medical, Inc. USA. Following recent conversation with this biotech company we expect to sign a formal license contract for the three patents obtained before April 2024. Furthermore, this company has signed a long-term (five years) agreement to stablish a new research laboratory at UAB campus, which will allow an active collaboration and technology transfer between the company and our group, and the generation of several workplaces at UAB campus. In the meantime, to advance in the valorization we are actively asking for financial support by asking for grants like PRODUCTE (AGAUR) in collaboration with GEBRO pharma in order to clarify aspects like (i) increase the biosafety profile, (ii) the conditions/doses for therapeutic efficacy; and (iii) the large-scale production of the therapeutic drug.

Isoformas de la proteína KL; Isoforma s-KL; Vectores de terapia génica; Seguridad farmacológica; Modelos murinos; Proceso de envejecimiento; Capacidades cognitivas; Neurogénesis adulta; Hipocampo; Procesos inflamatorios; Capacidades físicas; Reducción de la fibrosis; Regeneración muscular; Osteoporosis; Parámetros microestructurales; Esperanza de vida; Modelos en primates; Mejora cognitiva en primates; Eficacia terapéutica; Calidad de vida; Longevidad; Artículos científicos; Patentes; Interés industrial farmacéutico; Ensayos clínicos.