Carsten Bönnemann Lab

Oftentimes, treatment options are limited or nonexistent for children diagnosed with genetic disorders of motion and sensation, such as motor and sensory neuron disease or muscular dystrophies. To increase therapeutic opportunities, we must deeply characterize these diseases on the genetic/genomic, biological and clinical level to determine which precise therapeutic approaches might work as well as determine what information is needed to launch preclinical and clinical trials.  

We have developed cellular and preclinical model systems to accurately characterize the mutational mechanisms and biological consequences of neurogenetic diseases. Conducting preclinical studies using the most representative model systems allows us to conceive and test viable genetic therapeutic strategies and address specific variants or whole classes of mutations. Such strategies can be RNA directed (e.g., splice modulation with antisense oligonucleotides or allele specific knockdown using siRNA) or involve gene addition (e.g., adeno-associated viral (AAV) vectors or CRISPR technologies such as base and prime editing). 

Augmenting our genetic discoveries, we also develop natural history studies to understand how causative variants relate to the evolution of disease over time in distinct populations. In the diseases we study, we also validate outcome measures to develop clinical endpoints — crucial information that lays the foundation for understanding the course of disease and measures what constitutes clinical improvement in a clinical trial. Natural history studies deepen our understanding of disease and provide the baseline data required to initiate and conduct successful clinical trials. 

Our lab has been critically involved in the development of precision therapeutics for clinical trials. One such therapeutic was tested as a first in-human intrathecal AAV treatment for giant axonal neuropathy, an aggressive early onset neurodegenerative disease caused by biallelic loss-of-function variants in the gigaxonin (GAN) gene. Our approach utilized a self-complementary AAV vector containing a GAN transgene to add the normal sequence to the nerve cells without functional gigaxonin. Results showed this approach may benefit children diagnosed with this typically fatal disease, and we continue to explore the possibilities of this gene therapy as well as additional ones under development, such as for congenital myasthenic syndromes.  

Developing therapies for diseases affecting small patient populations has historically been challenging. Focusing on adaptable therapeutic approaches that can be applied across multiple motor neuron diseases has the potential to maximize impact.