Scientists from the Nencki Institute of the Polish Academy of Sciences have developed an experimental targeted therapy for autism. Their discoveries constitute a breakthrough in understanding how to alleviate the symptoms of this complex disorder. The findings have just been published in the scientific journal Molecular Psychiatry.

Doctor Alicja Puścian and the team conducting research under the supervision of Professor Ewelina Knapska at the BRAINCITY Center of Excellence for Neural Plasticity and Brain Disorders at the Nencki Institute of the Polish Academy of Sciences showed that experimental therapy targeted at the specific symptoms of autism is not only possible, but also effective.

- Autism, or more precisely, autism spectrum disorder (ASD), is a set of deficits that manifest in patients in various configurations and with varying severity. Everyone is different, there is no one universal phenotype. To fully address a given problem in the functioning of patients, "tailor-made" therapeutic solutions are needed - explains Dr. Alicja Puścian.

Among the long-standing challenges in contemporary psychiatry is the development of effective, mechanism-based therapies for neurodevelopmental disorders such as autism. Due to limited understanding of underlying causes leading to diverse disease manifestation, targeted intervention methods are practically absent. Even in diseases of a well-known genetic origin, such as Fragile X Syndrome (FXS) - the most common monogenetic cause of inherited autism - symptoms vary from patient to patient but the existing therapeutic solutions do not address this issue.

The two core groups of autistic symptoms are a) deficits in social interactions, including the inability to effectively communicate with others, and b) cognitive impairments. Notably, patients may display different symptoms of varying intensity. In fact, in some cases, autists only manifest cognitive deficits, without social impairments, or the other way around. Thus, to accelerate the search for effective treatments, we need to shift our focus toward the appreciation of the individual phenotype, which better reflects the reality of patients and their families.

Using mouse models of autism, that is, animals with a genetic defect found in patients, scientists from BRAINCITY designed a study in which they combined many advanced scientific methods: designer molecule delivery system, fully automated behavioral testing, long-term potentiation recordings, and high-resolution electron microscopy. Puścian et al. show that central amygdala (brain structure involved in our ability to learn)-targeted delivery of TIMP-1 protein, not only ameliorates severe cognitive deficits but also normalizes circuit physiology and ultrastructure of neurons, and synapses (connections between the nerve cells).

TIMP-1 is the inhibitor of matrix metalloproteinases, among them most notably matrix metalloproteinase 9 (MMP-9). It is an enzyme critical for neuronal plasticity that is the ability of the brain to adapt to the challenges of the changing environment. The enzyme is over-translated in FXS which contributes to the onset of autistic symptoms, including cognitive impairments. It is noteworthy, that the applied therapeutic strategy has no impact on the impaired social behavior of the FXS model mice, corroborating the symptom-specificity of the proposed approach, which was the goal of the study. Thus, the presented discoveries confirm that by targeting specific molecular mechanisms within the well-defined neuronal circuits it is feasible to address the individual symptoms.

The critical role of MMP-9 hyperactivity in the manifestation of FXS symptoms sparked several attempts at its downregulation in patients. Although research unequivocally supports that MMP-9 inhibition is a promising therapeutic strategy for FXS, currently the only clinically available treatment is the administration of minocycline, antibiotic with pernicious side effects that cannot be considered a conceivable permanent therapy. The research of the Knapska group constitutes a first mechanism-based, targeted therapeutic approach that also holds the promise of having no side effects. The results of their research are therefore of great importance for the fields of basic and clinical neuroscience.

- Our research illustrates how the combination of state-of-the-art methods in behavioral studies, neurobiology and pharmacology can be an effective way to make discoveries that provide a solid basis for further applied research - emphasizes Prof. Knapska.

Indeed, the research of Puścian et al. goes beyond addressing the specific cognitive problems relevant to the autistic phenotype and may serve as a blueprint for the targeted, symptom-specific, and mechanism-based strategies to remedy particular aspects of neurodevelopmental, neurodegenerative, and psychiatric disorders, such as Attention deficit hyperactivity disorder (ADHD), Alzheimer's disease or schizophrenia.

More information: https://www.nature.com/articles/s41380-022-01527-5