(7y) Transcriptome-Guided Cell and Gene Therapy Strategies to Treat Neurodegeneration

Neurodegenerative disorders affect large patient populations and cause enormous suffering and socio-economic burden. Every year in the US alone, several million patients suffering from neurodegenerative disorders cost the US economy billions of dollars in healthcare and lost economic productivity. Typically, these disorders lack cures and effective long-term treatments, and as a result patients often succumb to disease 10-20 years after onset. Therefore, new treatment strategies are urgently needed to address the growing burden of neurodegenerative disorders in an increasingly aging population. Stem cell and gene therapy based strategies, when properly designed and implemented, can be powerful treatment options. However, limited understanding of stem cell biology and of target cell populations in vivo often hampers such efforts. Fortunately, recent improvements in RNA sequencing can offer increased understanding of cell populations at a single-cell resolution. Leveraging my interdisciplinary training in engineering and biology, I aim to develop a multifaceted approach to treat neurodegenerative disorders using single-cell transcriptomics to guide biomaterial, gene, and cell-based treatment technologies.

Research Experience:

In my doctoral work, I developed non-viral, lipid based vectors for targeted gene delivery to cancer tissue. The optimized vector achieved high target specificity with minimum off-target effects in vitro and in vivo. In my postdoctoral work, I diversified my skillset with additional tools relevant to disease treatment. First, to help meet the high demand for transplantable cells for cell replacement therapy (CRT), I developed efficient, scalable methods to generate region-specific neurons from human pluripotent stem cells (hPSCs) using a biomaterial scaffold. In parallel, to address some of the major challenges facing successful CRT, I developed cell-instructive biomaterial scaffolds to enhance survival, dispersion, and integration of transplanted neurons. These strategies significantly improved CRT treatment outcomes in rodent models of Parkinson’s disease and Huntington’s disease. Finally, I used cutting-edge RNA sequencing technology to investigate the effect of culture platforms on stem cell behavior at the single-cell level. Thus, armed with tools to enhance gene and cell therapies, I am excited to develop multifaceted, combinatorial treatment strategies for neurodegenerative disorders.

Education:

B.S., Chemical Engineering, Biology, MIT (2007)

Ph.D., Chemical Engineering and Materials Science, University of Minnesota (2013)

Ph.D. Dissertation:

A Platform for Next-generation Cancer Therapies: Multi-targeted Non-viral Vectors for Site-specific Gene Delivery and Expression.

Supervised by Prof. Efrosini Kokkoli, Department of Chemical Engineering and Materials Science, University of Minnesota

Post-doctoral projects:

a) Developing a hyaluronic acid based transplantation scaffold to enhance post-transplantation survival, dispersion, and integration of hPSC-derived dopaminergic neurons to facilitate cell replacement therapy in a rodent model of Parkinson’s Disease.

b) Using hPSC-derived striatal cells generated in a 3D biomaterial to evaluate cell replacement therapy in a progressively degenerating mouse model of Huntington’s disease.

c) Using single-cell RNA sequencing to characterize the effect of culture platform on stem cell population heterogeneity.

Supervised by Prof. David V. Schaffer, Department of Chemical and Biomolecular Engineering, University of California, Berkeley

Grants:

California Institute of Regenerative Medicine (CIRM) Postdoctoral Fellowships 2014, 2015 (Both successful)

CIRM RT3 07800 2015 (Helped PI; Successful)

NIH R21 2016 (Helped PI; Unsuccessful)

Selected Publications (5 of 15 total):

1. M.M. Adil, Z.S. Erdman, E. Kokkoli, Transfection mechanism of polyplexes, lipoplexes and stealth liposomes in α₅β₁ bearing DLD-1 colorectal cancer cells, Langmuir, 30 (2014) p3802-3810
2. M.M. Adil, G.M. Rodrigues, R. Kulkarni, A. Rao, N. Chernavsky, E.W. Miller, D.V. Schaffer, Efficient derivation of hPSC-derived midbrain dopaminergic neurons in a fully defined, scalable 3D biomaterial platform, Scientific Reports, 2017 7:40573
3. M.M. Adil*, T. Vazin*, B. Ananthanarayanan*, G. M. Rodriques, S. Kumar, D.V. Schaffer, Engineered hydrogels increase the post-transplantation survival of encapsulated hESC-derived midbrain dopaminergic neurons, Biomaterials, 136(2017) 1-11
4. M.M. Adil, T. Gaj, A. Rao, R Kulkarni, C.M. Fuentes, G.N. Ramadoss, E.W. Miller, DV Schaffer, hESC-derived striatal cells generated using a scalable 3D hydrogel promote recovery in a Huntington’s disease mouse model, In revision
5. M.M. Adil, T. Ashuach, N.E. Chernavsky, G.N. Ramadoss, S. Dudoit, D.V Schaffer Single-cell RNAseq reveals culture platform dependent stem cell heterogeneity, In preparation

Future Research

The overarching goal of my lab will be to facilitate treatment of neurodegenerative disorders utilizing biologically-informed engineering strategies. Specifically, I will take three separate, initially independent, routes to address this challenge:

1) Identifying optimal cells for cell replacement therapy. CRT is a promising strategy to address neurodegenerative disorders, however clinical efficacy of this approach has only been demonstrated for Parkinson’s disease (PD). For many other incurable neurodegenerative diseases, especially ones affecting the striatum, the optimal composition of transplantable cells for successful CRT is currently unknown. One focus in my lab will be to identify the transcriptomic signature of human pluripotent stem cell (hPSC)-derived populations which can facilitate CRT in striatal neurodegenerative disorders. Subsequently, this transcriptomic information will guide generation of appropriate cell types for effective CRT in striatal neurodegeneration.

2) Biomaterial cues to guide stem cell fate. Effective control over the stem cell fate will facilitate a range of biomedical applications including CRT. However, many aspects of stem cell biology are still poorly understood, resulting in heterogeneity in stem cell cultures and low directed differentiation yields with poor reproducibility. Recently, there is increasing evidence that material microenvironments can have profound effects on stem cell fate. In my postdoctoral work, we demonstrated that culture within a defined 3D material can limit unwanted differentiation, increase proliferation, and improve yield of directed differentiation. Additionally, single-cell RNA sequencing revealed platform-specific transcriptomic signatures. Guided by this transcriptomic knowledge, my lab will aim to identify specific material cues that control stem cell fate. Ultimately, this knowledge will inform materials design for effective stem cell differentiation and transplantation in CRT applications.

3) Targeted gene delivery to the striatum. Cell replacement therapy, while a promising strategy to treat neurodegenerative disorders, may benefit from combinatorial treatment schemes to maximize treatment benefits. My postdoctoral work showed that while transplanted striatal cells alleviated Huntington’s disease symptoms for a period of time, rodent models eventually succumbed to the disease as a result of progressive neurodegeneration. My lab will investigate if therapy may benefit from additional approaches to halt degeneration and enhance graft survival. Leveraging my doctoral training, we will focus on developing effective non-viral vectors to deliver therapeutic genes specifically to supporting cells such as striatal astrocytes, with targeting strategy informed by the transcriptomic profile of the target cells.

In the long-term, I aim to incorporate findings from each of these three tracks into an optimized combinatorial strategy to address striatal neurodegeneration. The multidisciplinary nature of this proposed research provides many opportunities for collaboration, especially with computational and neuroscience labs.

Teaching Interests:

Among the classes in my academic career, I have gained the most from the ones that encouraged critical thinking, interactive learning, and creative problem-solving, while drawing parallels to real-life scenarios with the occasional, relevant anecdote. I strive to implement such features in the classes I will teach.

I taught core Chemical Engineering undergraduate courses as a teaching assistant at the University of Minnesota, where responsibilities included classroom lectures in discussion sections. Additionally, I mentored nine undergraduate students (two during my graduate school and seven during my postdoctoral years) in research; six of my mentees co-authored publications with me, three students went on to medical school, and three students are in graduate school. Several of my mentees completed their undergraduate honors theses under my direct supervision. Furthermore, I have mentored two graduate students on semester-long rotation programs in the lab. Through my undergrad (MIT) and graduate (University of Minnesota) education in leading Chemical Engineering departments, I am well-trained to teach common core curriculum courses, and possess extensive experience in research mentorship. Additionally, I am interested in developing an interactive graduate/senior undergraduate level course to teach and discuss the latest engineering approaches in cell and gene therapy.