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Neurodegenerative Diseases

Amyotrophic Lateral Sclerosis (ALS)

UMMS has a fantastic set of researchers conducting cutting-edge basic, translational, and clinical investigations into ALS.  These investigators work independently and also in subsets to identify genetic causes of ALS (Landers, Brown; NCT01459302), to understand disease mechanisms using cellular and animal models (Bosco, Gao, Hayward, Landers, Xu), and to develop novel therapeutic strategies (Brown, Mueller, Khvorova, Xu) by disrupting expression of disease-causing genes.  These therapies rely on administration of either adeno-associated virus (AAV)-based molecules or highly modified, synthetic nucleic acids targeting specific sequences, a strength at UMMS due to the Horae Gene Therapy Center and the RNA Therapeutics Institute.  In animal models, these strategies provide long-lasting and effective gene ‘knockdown’ and therapeutic improvement.  UMMS has initiated unprecedented trials to assess the effectiveness of these therapeutic approaches in patients with ALS. Dr. Brown and colleagues are also participating in assessing the safety and efficacy of a novel, stem-cell-based therapy (NTF-secreting mesenchymal stromal cells; NCT03280056).

Basic science work related to ALS includes work by Elisabet Mandon, Jill Zitzwitz, and Bob Matthews examining the impact of mutations in ALS-relevant proteins on their protein folding, interaction and function.

Alzheimer’s Disease

Evgeny Rogaev identified mutations in presenilin-1 and presenilin-2 associated with early-onset familial Alzheimer’s disease in 1995 (PMID: 7651536). His group continues to study molecular and genetic aspects of Alzheimer’s disease.

Doug Golenbock has developed a novel theory of Alzheimer’s disease pathogenesis, related to immune system function, and this animal-based work is now being carried forward in collaboration with Kensuke Futai.  Their interdisciplinary project “Roles of inflammasome-dependent cytokines in Alzheimer's Disease and Seizures” received a 2018 Riccio Fund for Neuroscience Award.

Alzheimer’s pathology is seen in virtually all cases of Down’s Syndrome (trisomy 21); Dr. Jeanne Lawrence is investigating mechanisms to silence the third copy of chromosome 21 in Down’s syndrome, thus preventing its pathological consequences.

Finally, Dr. Christelle Anaclet is determining whether sleep-promoting manipulations improve cognitive function in aging mice and in mouse models of Alzheimer’s disease.

Huntington Disease

Huntington’s Disease is an autosomal dominant neurodegenerative disease caused by expansion of a CAG nucleotide repeat within the Huntington gene.  The mutant protein lead to dysregulation of a variety of cellular processes, including neuronal cell death that is most concentrated in brain areas controlling cognitive function and movement.  A strategy for treating the disease at its root cause is to shut off production of the mutant protein.  Basic work into RNA interference as an approach to silence HTT expression, including the potential for allele-specific silencing, was conducted by Drs. Zuoshang Xu, Phil Zamore, and Neil Aronin.

Dr. Neil Aronin has been studying Huntington’s Disease for over 30 years, and that perseverance is paying off.  Together with experts in gene silencing (Anastasia Khvorova, Chris Mueller, and Jonathan Watts), Aronin’s group has developed therapies effective at silencing the Huntington gene in animal models and are rapidly approaching clinical studies of these potential therapeutics. 

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