Cure SMA Awards $300,000 Grant to Kevin Hodgetts, PhD, The Brigham and Women’s Hospital

Cure SMA has awarded a $300,000 preclinical drug discovery grant to Kevin Hodgetts, PhD, at the Brigham and Women’s Hospital, for his project, ” Pre-Clinical Development of LDN-5178 for the Treatment of SMA.”

This grant will be conducted by two academic research teams working together to identify new treatments for SMA. The two teams are led by Prof. Kevin Hodgetts at the Laboratory for Drug Discovery in Neurodegeneration (LDDN) at Brigham and Women’s Hospital, an affiliate of the Harvard Medical School, and Prof. Elliot Androphy at Indiana University.

The two academic research teams work together on the optimization of novel small molecules as activators of SMN2 protein. With this funding, they will continue the development of their lead series of compounds that increase the half-life and accumulation of normal SMN protein. These lead compounds have been shown to increase SMN protein in brain and extend survival and motor function in a mouse model of SMA.

In this proposal, the research teams will perform pre-clinical safety and toxicity studies on their lead molecules to ready them for Investigational New Drug (IND) submission.

Meet Dr. Hodgetts

Who are you?

I am a medicinal chemist working to discovery new molecules for the treatment of SMA. A medicinal chemist’s goal is to understand the medicinal effects of a drug, its metabolism and side-effects. This is done through the synthesis of potential drugs, and by studies investigating the drugs’ interactions with biological targets. Armed with this information, medicinal chemists design, optimize and develop molecules for use as drugs. I was trained as an organic chemistry at universities in England, the US and Ireland, and have since spent over 15 years in industry focused on the discovery of drug treatments for diseases of the central nervous system, including schizophrenia, depression and pain.

How did you first become involved with SMA research?

In 2012, I joined the Laboratory for Drug Discovery in Neurodegeneration (LDDN) at Brigham and Women’s Hospital. Since then, I have worked in close collaboration with Professor Elliot Androphy at Indiana University on new drug discovery strategies for the treatment of SMA. Prof. Elliot originally discovered the role of exon 7 splicing in the SMA back-up gene SMN2, a key finding that contributed to the discovery of Spinraza. We are now looking for new molecules that work differently than Spinraza or enhance the efficacy of Spinraza for the treatment of SMA. We originally discovered two molecules that increased protein from the SMN2 gene in two different ways: one increased the stability of SMN protein; while the other increased transcription, the first step in gene expression, of SMN2. As part of our investigation into these compounds, we discovered they were unsuitable for use in mouse models due to their low aqueous solubility and moderate stability. To overcome these characteristics, we used “medicinal chemistry optimization” – changes to the structures of each molecule – to improve the efficacy, solubility and stability of our molecules.

What is your current role in SMA research?

Through medicinal chemistry optimization, we identified new molecules with properties suitable for testing in mouse models of SMA. My lab is making the molecules on a large scale and with high purity for testing in SMA mice in the labs of Profs. Androphy and Christian Lorson at the University of Missouri. During the Cure SMA funded project, I will manage the pre-clinical studies required for the development of the best molecules, including formulation, pharmacokinetics and safety.

What do you hope to learn from this research project?

This funding will be used to continue the development of our lead series of compounds, performing pre-clinical pharmokinetics and toxicity studies, to ensure that they are as safe and effective as possible prior to entering clinical trials.

How will this project work?

We have identified lead compounds that increased SMN protein in brain and extended survival and motor function in a mouse model of SMA. In addition, we discovered in test tube experiments the use of our leading compounds, in combination with other SMN increasing agents (e.g., splicing modifiers), gave a synergistic increase in SMN protein. With this funding, we will perform pre-clinical pharmokinetics and toxicity studies on our lead molecules prior to IND submission.

What is the significance of your study?

If we can translate our test tube finding, that our compounds work synergistically with SMN increasing agents such as Spinraza, to first mice and then humans, it potentially would reduce the needed quantity and frequency of administration of Spinraza, resulting in greater therapeutic response and reduced occurrence of side effects.

Drug Discovery Funding

This grant to Dr. Hodgetts is part of $600,000 in new translation drug discovery funding that we’re currently announcing.

This grant was generously funded by a donation made to Cure SMA anonymously in honor of William N. Kanehann. We are grateful for this amazing donation in memory of Billy’s life.

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